America Votes to Decriminalize Drugs

first_imgIt’s Wednesday, July 3. astead herndon— and the violent crime that often associated and came with them. On its most literal level, it was two top-tier Democrats having the most confrontational, direct moment we’ve seen in the primary so far. astead herndon— a Democrat who understands black communities and has personal and deep relationships in those communities, but as a Democrat who can also unite the kind of outer portions of the state, which saw those issues very differently. archived recordingIn April, after the murder of Martin Luther King, the National Guard was called out in several cities to put down riots. One of these cities was Wilmington, Delaware. But now, in Wilmington, the National Guard is still on duty. And the governor, Charles Terry, has no plan to send it back. astead herndonThe head of the Congressional Black Caucus spoke out against it. Representatives like Bobby Scott said they knew that the kind of increase of police in these neighborhoods would cause detrimental effects.michael barbaroRight. So what turns out to be, over time, the actual impact of all of these bills, including the biggest of them all, that 1994 crime bill, in the years that followed?astead herndonThe undeniable impact is an explosion of America’s prison population that has disproportionately affected black and brown communities. So coming out of the ‘80s and ‘90s, you have a pretty clear articulation from then-Senator Biden that cops and the expansion of cops is a preventative measure. archived recording (joe biden)Before I start, I’d like to say something about the debate we had last night. And I heard, and I listened to, and I respect Senator Harris. But we all know that 30 seconds to 60 seconds on a campaign debate exchange can’t do justice to a lifetime committed to civil rights. astead herndon— the “three strikes and you’re out” kind of policy — archived recordingIt’s going nationwide, especially among the young, a drug so pure and so strong, it might just as well be called crack of doom. astead herndon— where, if you had three instances of drug offenses or violent drug offenses, it would be an instant life sentence. astead herndonIn 1984, that establishes mandatory minimums. In ‘86, the Anti-Drug Abuse Act creates harsher sentences for crack than powder cocaine. And it kind of builds up into the early ‘90s, when Bill Clinton is elected president, the ‘94 bill — astead herndonBut there’s other times when he sounds very much like many of the black leaders in Wilmington who say, I don’t know if I like this remedy, but I do know that the issue of integration is really important. So he’s kind of firmly in the middle. And that kind of middle ground is something we see him stake on a number of issues, most notably crime, where he takes the kind of position and relies on those personal relationships with black communities, while, according to his critics, legislating in the interest of white ones.[music]michael barbaroWe’ll be right back. So Joe Biden takes the middle ground, or the middle ground for that time, on busing. How do we then see that in his approach to crime?astead herndonThis one’s a little different, because while Biden on busing was seen as kind of emblematic of the larger Democratic stance, with crime, he was really kind of pushing the boundaries. At that time, particularly in the ‘80s and ‘90s, was a kind of moral panic happening throughout the country — astead herndonAnd Joe Biden runs for Senate in 1971 as a new type of Democrat — archived recording (joe biden)That Barack and I finally reduced the disparity in sentencing, which we had been fighting to eliminate, in crack cocaine versus powder cocaine. It was a big mistake when it was made. We thought we were told by the experts that, crack, you never go back. It was somehow fundamentally different. It’s not different. But it’s trapped an entire generation. astead herndon— around the explosion of drugs in cities — astead herndonWe know that Joe Biden very rarely apologizes. But it was not until this year that you really have an articulation from Vice President Biden that he played a role as a senator in creating some of these disparities. michael barbaroWell, so Astead, what do you make of how defensive Biden has been to these criticisms and these questions about his legacy, rather than acknowledging, a lot has changed since then. I was doing what I thought was best in the moment. I now see, I now understand that it played out differently than I expected.astead herndonThis is a question I’ve thought a lot about. If by the early 1990s, it was clear to the cops on the ground in Wilmington that the tough-on-crime measures didn’t work, that the disparities that were created in the ‘80s between crack and cocaine were disproportionately hurting black communities, why did it take until this year for Joe Biden to acknowledge it himself? And we don’t have clear answers to that. archived recording (joe biden)I applied to the city of Wilmington for a job, and I was the only white employee here. And I learned so much. And I realized that I live in a neighborhood where I could turn on the television, and I’d see and listen to Dr. King and others. But I didn’t know any black people. No, I really didn’t. You didn’t know any white people either. That’s the truth. But it also felt like this was about the details of a specific policy that Biden was a part of. And most of us probably don’t really understand what his intentions were or what the context of that policy was. So take us back to that time. Where was Joe Biden in his political career?astead herndonWell, Joe Biden began as a lawyer in Wilmington and, eventually, a city councilor in the county. And he was emerging at a really racially contentious time within the city and state. astead herndonYou get a court order in the late ‘70s that says that Delaware schools are too racially segregated, and they must form a plan for racial integration. And a plan is instituted by the courts that says, from the city in Wilmington, which is majority black, and the suburbs outside of it, that both those groups of students were for some portion of their schooling going to have to bus to the opposite community. So for the kind of inner city students, which are majority black, they were going to have to go out to the suburbs for six years. And the outer suburbs would have to come into Wilmington schools for about three years. So this becomes the plan that’s put in place that inflames those racial tensions on both sides of the state.michael barbaroAnd what is Biden’s opposition to that specific solution?astead herndonThat the idea of integration was not a problem, but it was how the courts were forcing them to go about it. You have to think — if you were a parent in the suburbs, which is almost exclusively white, who had made that choice for your family almost entirely around the school district that your child was supposed to go into. And then there is a court order that comes down that says not only are different people coming to that school, but that your child is going to be put on a bus to a different school. That is the logic that those parents used to oppose the idea of busing. And so at one point in 1975, Joe Biden says, the real problem with busing is you take people who aren’t racist, people who are good citizens, who believe in equal education and opportunity, and you stunt their children’s intellectual growth by busing them to an inferior school. And you’re going to fill them with hatred.michael barbaroSo Biden is sympathizing with white parents in the suburbs who are suddenly feeling dislocated by this decision. But what about black parents in this city whose children would be bused to these theoretically better schools in the suburbs? What is Biden saying to them?astead herndonThis is an important point. Although the kind of white suburbs were almost uniformly against busing, somewhat because of the method and sometimes because of pure racism, in black communities, particularly in Wilmington, there is not universal agreement on this issue. There is universal consensus that integration is important and that their schools had not been adequately funded or not been adequately supported by the state. But when you look at polling and when you talk to people at the time, the actual issue of busing is controversial. Remember, these parents themselves had to send their children further away into neighborhoods and communities that may have not always been welcoming to those students. So it wasn’t universally loved. In one poll, about 40 percent of black parents supported the idea, 40 percent were against it, around 20% were unsure. Joe Biden tries to take a nuanced position, where sometimes it seems like he is a vocal opponent of the idea of busing and that he is signaling to the kind of white Delaware that he is their advocate. astead herndonBut in the bigger, more abstract view, these were two different generations of Democrats. One, a barrier-breaking, younger black senator, pushing the old guard, the senator who came in the 1970s, who had relationships with segregationists and avowed racists. She was pushing him on racial issues and trying to hold him accountable for how the Democratic Party has handled issues of race for decades leading up to this point.michael barbaro- Advertisement – astead herndonJoe Biden takes the position, as many other politicians did at that time, that they were not opposed to the idea of integration. What they’re opposed to was the remedy. astead herndonHe felt that the kind of presence of police officers, the increased presence of police officers in these communities, would inherently mean that crime would go down. As the years have gone on, it has become clear that the actual effect was not that, but was the disruption of the communities themselves. When I was in Wilmington talking to folks there, they were saying by 1994, it was already clear that the tough-on-crime kind of measures of the ‘80s weren’t working on the streets. It was not decreasing crime, but more importantly, it was causing a kind of incarceration effect that didn’t have the terminology for mass incarceration that we now call it, but it was clear that communities were getting ruptured by the increase in sentences and the increased focus on tough-on-crime measures.michael barbaroAnd of course, the legacy of busing is that we’ve seen a resegregation of the U.S. school system, because the job was never really done.astead herndonExactly. There is a narrative that busing failed, but the truth is kind of murkier. Busing, as a policy, often did achieve its goals and racially integrate the places it was instituted. What failed was the political will to keep those measures in place that made integration happen and to see racial integration of schools as a necessary problem to solve. So in the last decades, you have not only overturned to pre-busing segregation levels, but in some places, you have racial segregation in schools becoming even worse than they were, or just as bad as they were, at the time of Brown v. Board of Education.michael barbaroSo Astead, it seems like what we’re seeing in the debate last week, in this exchange between Harris and Biden, was that Biden is going to have to confront these past policies as their legacies are understood in the current moment. And that means complicated legacies with real implications, many of them quite negative for the black community.astead herndonJoe Biden is being — his whole record is being examined in new ways. He’s run for president twice before, but never as a front-runner and never as someone who enjoys this amount of support among black communities. Remember, this is still the vice president to the first black president. This is still the person who is seen, oftentimes, as the most likely to beat President Trump in the Democratic Party, which black communities have often seen as their number one goal. So he’s enjoying this kind of support, robust support, among black communities, while at the same time, his rivals are trying to use his record, particularly on busing and crime, to wrest away those votes. And I think that’s a really interesting question, is will these moments, like the one Senator Harris made happen in the debate, will they start to chip away at that image of him as a champion and an advocate for black communities? As people come to understand the record and as people come to understand the context of Delaware at the time, will he be seen as someone who was navigating a difficult racial terrain or as someone who kept black people close, but fundamentally legislated in the interests of white communities?michael barbaroAnd so the question is, will voters evaluate him for what he was trying to accomplish in the ‘70s, and the ‘80s, and the ‘90s, or for what we now understand the impact of those bills to have been up through today? I wonder if you have any sense of how black voters are seeing that from your reporting.astead herndonI spent a lot of time in South Carolina, where we have the biggest population of black voters in the early states. And Joe Biden enjoys a large amount of goodwill in those places. What that is not is a deep connection to Joe Biden as an individual. As I heard someone say recently, his support is wide, but it’s thin. I think that people vote on a lot of different levels. Voting based on policy and record is one of them. Voting based on emotion, and feeling, and connection is another. And I think in this era for Democrats, and particularly for black Democrats who feel as if Trump has brought in a new era of white identity politics, there’s voting based on fear. And what you hear in South Carolina is not that they want to vote for Joe Biden because they believe in the things that he has done. But they see him as kind of an emergency fix to a much worse problem for them, which they believe is the presidency of Donald Trump.michael barbaroAstead, is what you’re saying the black voters may be more inclined to go with a safe choice, because in their mind, in this racial climate and in this political climate, the alternative, which is not winning the presidency, is far more threatening than a Democratic candidate with a debatable historical record on race?astead herndonYep. And I think it’s important to make distinctions when we talk about black voters. We particularly see that kind of calculation among older black voters and black voters who are in the South. Now among younger voters, we see a bigger willingness to reject Joe Biden because of some of those records and to embrace candidates who are talking more explicitly and openly about structural changes to create racial equity. But among the older voters, who remain the real heart and soul of the black vote and a sizable portion of the Democratic electorate, it’s that calculation of safety that’s really helping Joe Biden right now. But we should also say that among those older voters, many of them can remember 1994 and remember the 1980s and may have themselves supported these bills and seen their thinking change as well. And I think that’s the important thing to not forget, is just as Joe Biden has evolved, so have many of these people. And I’ve talked to people who don’t see what he did as particularly invalidating, frankly, because they have experienced that same evolution. And sometimes, I have talked to people who said that ‘94 crime bill ruined their homes, and they also say they can’t wait to vote for Joe Biden in the primary. archived recording (bill clinton)Thank you, Mr. Vice President, for your introduction and for your labors on this bill. archived recording (joe biden)Politicians have done such a job on the people that the people don’t believe them anymore. And I’d like a shot at changing that. astead herndonIt was part of his identity and part of his brand that he cared about civil rights, understood the plight of African-Americans in Wilmington, but also, he understood that kind of outer white Delaware was really motivated around grievance at the time. In 1971, a group of black students had filed a lawsuit in hopes to get the schools to further desegregate. And so the question of school segregation and school integration was very much on the forefront of the state’s politics. And at the exact same time, that’s when the young Joe Biden makes his way to Capitol Hill.michael barbaroAnd what was Biden’s position when it came to desegregation? astead herndonAnd Biden, as someone who had come up in Wilmington, a community that was experiencing these things closely, he had black community leaders, neighbors of his, saying the issue was very important, but that they were looking at kind of root cause problems of why crime was happening. They were talking about issues like education or job opportunities and the like. When the outer Wilmington and the kind of all-white suburbs, you were hearing a more vocal cry for increasing cops, increasing prisons, and really cracking down on those tough-on-crime measures that came to the cities. So again, Biden is caught between political problem, but also one that’s divided pretty clearly on racial lines.michael barbaroAnd so what does he do? michael barbaroDo you think it’s possible that he might fear that if he apologizes, that that might weaken him more with moderate voters who don’t feel that Americans should have to apologize for that period, for those instincts, and for those policies?astead herndonI think that’s a big possibility. I also think Joe Biden was acting in what he believes was good faith, even at that moment, and what he thinks was the evidence in front of him and the context of the time. I think it’s important to always go back to Delaware with him. And in the moment that he comes up in, it is part of his personal and political identity that he was an advocate for the black communities and that he was performing a new role and, frankly, public service to those communities that white politicians had not done in that state. And so I think it’s bigger than just the political realities of right now and what apologizing would mean. To apologize would go to the heart of what his identity has been since he got in public office in the 1970s.michael barbaroMm-hmm. And he’s just not willing to apologize for that. Because in fact, he’s still proud of it.astead herndonThe evidence in front of us tells us that’s true. He was praising the crime bill just years ago. And he has called it, at some points, his greatest accomplishment. And he has shown a real resistance to the many opportunities that activists and other rivals have given him to say that those actions were a mistake.[music]michael barbaroAstead, thank you very much. We appreciate it.astead herndonThanks for having me.michael barbaroWe’ll be right back.Here’s what else you need to know today. On Tuesday, the Trump administration said it would end its attempts to ask about citizenship on the 2020 census, dropping the proposed question from the survey. The decision comes just days after the Supreme Court ruled that the administration had failed to offer a compelling explanation for including the question, which critics said was an attempt to discourage undocumented immigrants from filling out the census, and ultimately, skew the results of the census in favor of Republicans. And House Democrats have filed a lawsuit against the Treasury Department and the Internal Revenue Service, demanding access to President Trump’s tax returns. The lawsuit moves a months-old political dispute between Congress and the White House into the federal courts. At the heart of the fight is whether Congress has the legal right to review the president’s personal financial information. The White House says that such requests must be limited to materials needed to draft laws. House Democrats say that their powers are far broader and are not subject to second-guessing by the executive branch.That’s it for “The Daily.” I’m Michael Barbaro. See you on Friday, after the holiday. archived recordingThe truth is every major crime bill since 1976 that’s come out of this Congress has had the name of the Democratic senator from the state of Delaware, Joe Biden, on that bill. archived recording (joe biden)Where the court has concluded that a school district, a state, or a particular area has intentionally attempted to prevent black, or any group of people, from attending a school, the court should and must declare that to be unconstitutional and thereby move from there to impose a remedy to correct the situation. archived recording (bill clinton)“Three strikes and you’re out” will be the law of the land. archived recording (joe biden)In a nutshell, the president’s plan doesn’t include enough police officers to catch the violent thugs. archived recording (jesse jackson)This ill-conceived bill, fed by a media frenzy over crime, was on the fast track to the president’s desk for signature by Christmas. michael barbaroAnd what do we understand about how the black community back in Delaware felt about these tough crime measures at the time?astead herndonJoe Biden talks about, to this day, in his presidential campaign, they make a big point to say that the Congressional Black Caucus overwhelmingly voted for the bill and that black leaders at the time were very supportive of the bill. That is partly true. The Congressional Black Caucus certainly backed the bill after showing some initial wariness. The majority of its members voted for it. There were some vocal black mayors who were calling for these particular measures. But there were also some who were against it. astead herndonJesse Jackson spoke out against it. archived recording (joe biden)Not enough prosecutors to convict them, not enough judges to sentence them, and not enough prison cells to put them away for a long time. archived recording (bill clinton)We have the tools now. Let us get about the business of using them. astead herndonThere’s this split screen of Joe Biden that you often hear about when you talk to people in Wilmington. There is the neighbor who would go to black churches, would know the kind of leaders by name, and the issues they were advocating for. But then in Washington, you have a Joe Biden that is using those stories of Wilmington to kind of pass more tough-on-crime measures that some in that community say they weren’t asking for. In 1977, he first proposes mandatory minimums for drug sentences. And through the ‘80s, in his connection with Strom Thurmond, they end up passing a really kind of significant set of bills. archived recordingIt’s the devil — see, this cocaine ain’t nothing but the devil, and the devil was telling me to do it. archived recording (joe biden)I’m Joe Biden, and I’m a candidate for the United States Senate. archived recording (joe biden)And on the issue that the argument is about — and that is whether or not busing is, A, required constitutionally, and B, has a utilitarian value for desegregation — I come down on the side of A, it is not constitutionally required, and B, it is not a useful tool. archived recordingCrack, the most addictive form of cocaine, is now sweeping New York. archived recording (joe biden)If we want to have this campaign litigated on who supports civil rights and whether I did or not, I’m happy to do that. I was a public defender. I didn’t become a prosecutor. I came out, and I left a good law firm to become a public defender, when, in fact — [APPLAUSE] — when, in fact, my city was in flames because of the assassination of Dr. King. archived recording (jesse jackson)Spending several billion dollars on prisons and longer sentences is not the answer to reducing crime. michael barbaroAstead, to the average American watching the debates last week, what do you think that this now famous confrontation between Joe Biden and Kamala Harris seemed to be about?astead herndon- Advertisement – astead herndonJoe Biden himself tells a story about how he was the only lifeguard at a newly integrated pool in Wilmington. archived recording (joe biden)I haven’t always been right. I know we haven’t always gotten things right. But I’ve always tried. archived recording (joe biden)I have argued that the least effective remedy to be imposed is the busing remedy. michael barbaroFrom The New York Times, I’m Michael Barbaro. This is “The Daily.”Today: In the Democratic race for president, Joe Biden is being asked to confront a record on race that some in his party now see as outdated and unjust. Astead Herndon on the policies Biden embraced and how they were viewed when he embraced them.- Advertisement – archived recording (kamala harris)I do not believe you are a racist. And I agree with you when you commit yourself to the importance of finding common ground. But I also believe — and it’s personal. And I was actually very — it was hurtful to hear you talk about the reputations of two United States senators who built their reputations and career on the segregation of race in this country. And it was not only that, but you also worked with them to oppose busing. And there was a little girl in California who was part of the second class to integrate her public schools. And she was bused to school every day. And that little girl was me. So I will tell you that on this subject, it cannot be an intellectual debate among Democrats. We have to take it seriously. We have to act swiftly. – Advertisement –last_img read more

Trudeau and Macron speak after cartoon remark controversy

first_img– Advertisement – A teacher was beheaded in a Paris suburb after showing cartoons of the Prophet Muhammad to some of his pupils. On Tuesday, Mr Macron spoke by phone with the premier of the Canadian province of Quebec, Francois Legault, to thank him for his words of support in the wake of the attacks. But Mr Macron did not place a call to Mr Trudeau that day – seen as a snub by the French leader, especially as both men are viewed as like-minded political allies. Mr Trudeau expressed Canada’s solidarity with “the people of France” following the recent terror attacks. What was Macron’s reaction? Mr Trudeau’s remarks last week about freedom of expression were criticised in both Canada and France. – Advertisement – Mr Trudeau and Mr Macron spoke by phone on Thursday, suggesting the two leaders were mending fences over the remarks. What did Trudeau say last week? Mr Trudeau condemned the recent attacks in France, including a deadly knife attack on a church in Nice, the third suspected Islamist attack in the country in little more than a month. He added: “We do not have the right for example to shout fire in a movie theatre crowded with people, there are always limits.” read more

In a bright sign from Georgia, Democrats flip House seat in Atlanta’s long-Republican suburbs

first_imgFor a time, the GOP gerrymander worked exactly as intended. The new 7th District backed Mitt Romney by a strong 60-38 margin even as he was carrying all of Gwinnett County only 54-45, which was Team Red’s weakest showing in a presidential race since Carter won it back in 1976. National Democrats also didn’t make any serious effort to unseat Woodall, who seemed completely safe.However, things dramatically changed during the Donald Trump era in this well-educated and diverse suburb. Trump outright lost Gwinnett County 50-44, and while he did win the 7th District, his 51-45 showing in 2016 was a big drop from what the GOP was accustomed to. Woodall himself easily turned back an underfunded Democratic foe that year in a contest that attracted no outside attention, and he seemed ardently convinced that he would remain safe despite Trump’s drop. In May of 2017, Woodall even glibly said of his own race, “It’s gerrymandering that makes these things noncompetitive, right?” That obliviousness to his seat’s changing politics almost cost him reelection in 2018. Bourdeaux, a Georgia State University public policy professor, won the Democratic nomination after a crowded primary, and she proved to be a strong fundraiser. Woodall, though, didn’t run any ads for most of the campaign or even do many advertised campaign events. However, he got something of a wake-up call late in the campaign when Independence USA, a super PAC funded by former New York City Mayor and gun safety advocate Michael Bloomberg, dropped $913,000 on him in the final days of the race. Finally, on the Friday before Election Day, Woodall finally went up with his first TV spot.- Advertisement – Gwinnett County would continue to overwhelmingly support every Republican presidential nominee well into the first decade of the 21st Century, and the rapidly growing community was also a major source of strength for Team Red’s gubernatorial and Senate candidates during this time. The county also soon became very friendly turf for Republican congressmen. Woodall spent years working as an aide to local Rep. John Linder, who never had any trouble winning reelection during his nearly two decades in Congress, and Woodall himself faced no serious general election opposition when he ran to succeed his boss in 2010.Gwinnett County became more competitive during the 2000s, with John McCain carrying it just 55-45 four years after George W. Bush overwhelmingly won it 66-33, but that didn’t seem to matter much for Woodall. Republican mapmakers did all they could to make sure the 7th District remained safely red when they redrew the maps in 2011, and he was left with a redrawn seat that included just over 70% of Gwinnett County as well as the same portion of Forsyth County, a smaller but far more conservative area. (About 22% of Gwinnett County, including its more Democratic areas, was assigned to the safely blue 4th District, while the balance went to the dark red 10th District.)- Advertisement – Ultimately, while House Democrats didn’t make the gains in the suburbs they were hoping for, Bourdeaux pulled off a victory. This pickup came as once solidly Gwinnett County continued to move hard to the left: Joe Biden has dramatically improved on Hillary Clinton’s showing from just four years ago, and Democrats will also be looking for a strong performance here in January as they try to win as many as two U.S. Senate runoffs. Want more great elections coverage like this? Sign up for our free daily newsletter, the Morning Digest. Bourdeaux ended up losing to Woodall by just 433 votes in a performance that shocked both parties. It wasn’t an outlier, though: Democratic gubernatorial nominee Stacey Abrams, despite the taint of Republican voter suppression that marred her election, performed well in Gwinnett County and other Atlanta suburbs, and she even won the gerrymandered 7th District  by a 50-49 margin.Bourdeaux quickly made it clear that she’d be running again, and this time, both parties were aware that they’d have a fight in the 7th. Republicans reportedly weren’t keen on having Woodall stick around after he almost sleepwalked to victory, and the Atlanta Journal-Constitution reported in early February of 2019 that some unnamed GOP officials were pressuring him to “consider his options” for the cycle. Woodall seems to have gotten the message, and he announced his retirement days later.A number of candidates from both parties soon entered the race to succeed Woodall, but neither primary ended up going to a runoff. Bourdeaux’s opponent this time was Rich McCormick, an emergency room physician who received serious support from the far-right anti-tax Club for Growth. The general election also proved to be a very expensive affair, with the DCCC and House Majority PAC spending a total of $6.5 million on the Democratic side compared to $5 million from the NRCC and Congressional Leadership Fund.- Advertisement – – Advertisement –last_img read more

How Amanda Stanton Celebrates Merry Little Moments This Holiday Season

first_img– Advertisement – Grab your ornaments, candy canes and favorite Starbucks® holiday coffee because it’s officially the most wonderful time of the year! And even though this holiday season might look a little different than past, Amanda Stanton is proving that there are still plenty of reasons to be merry.Amanda’s first piece of advice? Celebrate the little things, like the joyful feeling of starting your day with your favorite cup of coffee. Amanda shares, “There’s nothing better than waking up in the morning and having your house smell like coffee. I like to switch it up between Starbucks® Holiday Blend and Peppermint Mocha,” both of which are available in either K-Cup pods or bags of roast and ground. Amanda adds peppermint creamer to create a simple yet delicious morning treat. When she’s feeling extra festive, she’ll top it off with some whipped cream to further get into the holiday spirit.- Advertisement – Secondly, Amanda suggests embracing the unexpected and turning holiday mishaps into new traditions. Amanda reflects on her own holiday memory that didn’t exactly start off as planned.“My parents were visiting me for Christmas. It was my first time ever making a turkey … it overflowed in the oven, it was a huge mess. We ended up just going to get Chinese food. It was a total fail, but we now have a new family tradition of getting Chinese food on Christmas.”Just like she and her family did, Amanda encourages fans to make their own merry little moments during the holidays, whether it’s video chatting with family, cooking a turkey for the first time or even just enjoying your favorite cup of Starbucks® coffee.- Advertisement –last_img read more

Singles Day: The billion dollar shopping event luring scammers

first_imgSingles Day: 3m people, 4,000 planes and shipsChina continues to bounce back from virus slump

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A giant screen shows sales information from Tmall, Alibaba's online marketplace

These stocks would benefit the most from a vaccine-driven economic recovery, Goldman says

first_img(This story is for CNBC Pro subscribers only.)Goldman Sachs believes the eventual arrival of a vaccine is expected to turbocharge the economic recovery and corporate earnings growth, and certain stocks stand to receive the biggest boost.The bank screened the S&P 500 for stocks with the lowest consensus 2021 earnings estimates relative to their realized 2019 profits. These names are expected to have earnings next year that are still less than half the level in 2019. Now with the economic recovery accelerating, this list of companies could see a drastic rebound in profit estimates from here and have the potential to lead the market gains going forward, Goldman said.- Advertisement – – Advertisement – – Advertisement – “For investors searching for individual stocks that would benefit most from economic recovery, we screened for companies where the largest gap exists between the forecast level of consensus 2021 EPS and the level of pre-pandemic profits in 2019,” David Kostin, the bank’s chief U.S. equity strategy, said in a note on Wednesday. The Wall Street Bull (The Charging Bull) is seen during Covid-19 pandemic in New York, on May 26, 2020.Tayfun Coskun | Anadolu Agency via Getty Imageslast_img read more

Genetic analysis ‘doubles’ data on avian flu viruses

first_imgFeb 7, 2006 (CIDRAP News) – US researchers recently published preliminary findings from their sequencing of 336 avian influenza (AI) viruses collected around the world, an effort they say has doubled the amount of public genetic data on avian flu viruses.The researchers from St. Jude Children’s Hospital in Memphis also say their analysis has uncovered one possible clue to the reasons for the severe illness and high death rate in humans infected with the H5N1 avian flu virus.The team, led by senior author Clayton W. Naeve, PhD, used a library of roughly 11,000 flu viruses, including about 7,000 avian flu viruses, collected over three decades by virologist Robert G. Webster, PhD, a member of the group.The 336 viruses they analyzed were gathered between 1976 and 2004 from ducks, gulls, shorebirds, and poultry in North America, Eurasia, and Australasia. Their analysis covers 2,196 new AI gene sequences and 169 complete AI virus genomes. The samples include all 25 known types of the two flu virus surface proteins, hemagglutinin and neuraminidase.”This information is a true gold mine, and we are inviting all of the miners to help us unlock the secrets of influenza,” Webster commented in a St. Jude news release.The team supplemented their analysis by including 2,143 AI virus gene sequences already available from GenBank, for a total of 4,339 genes. AI viruses have eight gene segments that code for 11 known proteins, the report notes. The authors developed phylogenetic trees for each of the eight gene segments to show their relationships across different virus isolates.To examine the variability of the viruses more closely, the authors developed a technique they call proteotyping, in which they identified gene variants with unique amino acid signatures. “Using this approach has allowed us to observe for the first time viruses sharing not only specific genes but genes coding for specific proteotypes,” the report says.Hemagglutinin and neuraminidase are highly variable because they are the main targets of the host immune system and constantly evolve to evade it, the report notes. But the researchers also found that the NS gene, which codes for two nonstructural proteins, called NS1 and NS2, is also highly variable. NS1 appears only in infected host cells, where it regulates many cell functions during infection and, according to considerable evidence, plays a role in virulence by blocking certain host antiviral genes, the article says.The team identified a particular ligand, or amino acid cluster that binds to other molecules, on one end of the NS1 molecule. By examining 1,196 NS1 sequences from avian, human, swine, and equine flu virus samples, the researchers discovered that all the avian samples had a certain amino acid sequence in this particular ligand, while most of the human samples had a different sequence.Thirty-eight of the human samples had sequences matching those found in the avian viruses, and most of those 38 were recent H5N1 viruses, the report says. The authors concluded that the human H5N1 cases have involved NS1 proteins with “avian”-type sequences at the identified ligand, whereas flu viruses from low-mortality human pandemics (1957 and 1968) had typically “human” sequences at that location.The report briefly describes two experiments the authors conducted to compare the ability of the avian and human NS1 proteins to bind to certain proteins, called PDZ domains, involved in many host cell processes. The results indicated that the avian NS1 protein is much more apt to bind to PDZ domains than the human NS1 is.”While the molecular consequences of these interactions are as yet unknown, it appears that avian NS1 proteins when introduced into human cells have the opportunity to bind to and disrupt many PDZ–domain protein mediated pathways that the human NS1 protein cannot,” the authors write.They suggest that disruption of these pathways may contribute to the high death rates in human H5N1 cases, though other genes and gene products are clearly involved. Further, they suggest, the NS proteins “may prove valuable as targets for antiviral therapy.”Virologist Yoshihiro Kawaoka of the University of Tokyo and Ujiversity of Wisconsin, Madison, said animal experiments are needed to assess the effects of the NS gene variations on pathogenicity, according to a Science news story accompanying the report. But he called the report a good example of using sequence information to develop new hypotheses.Obenauer JC, Denson J, Mehta PK, et al. Large-scale sequence analysis of avian influenza isolates. Science 2006 Mar 17;311(5767):1576-80 (Epub 2006 Jan 26) [Abstract]last_img read more

THE PANDEMIC VACCINE PUZZLE A seven-part series on the chances for immunizing the world against pandemic flu

first_imgEditor’s note: This article was originally published in CIDRAP News as a seven-part series running from October 25 through November 2, 2007. It investigates the prospects for development of vaccines to head off the threat of an influenza pandemic posed by the H5N1 avian influenza virus. The series puts advances in vaccine technology in perspective by illuminating the formidable barriers to producing an effective and widely usable vaccine in a short time frame.Part 1: Flu research: a legacy of neglectPart 2: Vaccine production capacity falls far shortPart 3: H5N1 poses major immunologic challengesPart 4: The promise and problems of adjuvantsPart 5: What role for prepandemic vaccination?Part 6: Looking to novel vaccine technologiesPart 7: Time for a vaccine ‘Manhattan Project’?Bibliography Part 1: Flu research: a legacy of neglectIt has been 10 years since the H5N1 strain of avian influenza first grabbed international attention by causing the death of a Hong Kong 3-year-old, the novel virus’s first known human casualty (see Bibliography: CDC 1997). In the decade since, the virus has torn across the globe, causing 332 known human illnesses and 204 deaths in 12 countries, according to the World Health Organization (WHO), as well as the deaths or preventive slaughter of hundreds of millions of birds.In that time, avian flu and the potential human pandemic it could cause have waxed and waned in public attention. Scientific attention to the H5N1 threat, though, has never wavered. Much of that attention has focused on finding a vaccine against H5N1, “the single most important public health tool for decreasing the morbidity, mortality and economic effects of pandemic influenza,” according to Dr. Gregory Poland, director of the Mayo Clinic’s Vaccine Research Group in Rochester, Minn. (see Bibliography: Poland 2006).But after almost a decade of research, a safe, effective, affordable, and abundant vaccine against H5N1 flu remains disappointingly out of reach. The search for a human avian-flu vaccine that could be developed and delivered in time to short-circuit a pandemic has been dogged by multiple obstacles across many sectors. They include patchy scientific knowledge, sparse government funding, thin manufacturing and packaging capability, and restrictive regulatory structures—along with the wily immunology of the H5N1 virus itself.Despite recent encouraging news from several clinical trials, the scientific—and financial and political—hurdles to producing a widely deployable vaccine remain dauntingly high. As the WHO admitted in its Global Pandemic Influenza Action Plan, published last year, “At the present time, if an influenza pandemic were to occur, the potential vaccine supply would fall several billion doses short of the amount needed to provide protection to the global population” (see Bibliography: WHO 2006).A chronic low priorityThe search for a pandemic vaccine was hobbled from the start by the relatively low priority placed on influenza research before the 1997 Hong Kong outbreak. Almost 80 years had passed since the 1918 pandemic, an outbreak that was globally traumatic but was largely, and strangely, overlooked by historians of the period (see Bibliography: Crosby 1989). For most, “pandemic” would have evoked not the estimated 100 million dead of 1918 but the approximately 1 million worldwide deaths in 1968-69, the mildest pandemic since modern records began—or the failed pandemic alarm sounded in 1976 after swine flu cases were discovered in Fort Dix, N.J., and the rash of adverse events triggered by the emergency vaccination campaign that followed.As a public health threat, flu had faded from federal, commercial, and thus public attention. A 1985 Institute of Medicine (IOM) report, “New Vaccine Development” (updated in 2000 as “Vaccines for the 21st Century”) urged fresh focus on flu-vaccine research but, coming as concern over AIDS began to crest, attracted no additional investment to flu (see Bibliography: IOM 1985, IOM 2000). Consumption of seasonal flu vaccine was relatively low: Americans received 54.9 million doses in 1995, according to data from the Centers for Disease Control and Prevention (CDC), and an additional 16.6 million were returned unused to manufacturers (see Bibliography: Santoli 2007). Lacking a strong public appetite for seasonal flu vaccine, and thus a reliable market, flu-vaccine manufacturers saw no reason to improve on the cumbersome egg-based production technology that had been used since the 1950s.”Influenza has not been treated with the degree of medical attention that the disease warrants,” Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID), warned in a 2006 commentary (see Bibliography: Fauci 2006). “There is not an adequate baseline of preparedness in the United States to deal with the potential of pandemic influenza.”Gaps in the knowledge baseRecent assessments by US and European experts have conceded that flu research still lags. A blue-ribbon panel convened last year by the NIAID recommended in a June 2007 report that “eight specific aspects of influenza research in which there are substantial gaps in knowledge” receive immediate attention. The areas included clinical and immune responses to flu, flu epidemiology, animal models for flu research, antivirals, diagnostic assays, and, notably, vaccines, of which the group said: “Development of improved influenza vaccines is a key priority for the control of both seasonal and pandemic influenza” (see Bibliography: NIH 2007).Echoing that report, the European Centre for Disease Prevention and Control’s technical advisory groups on human H5N1 vaccines warned in August that 10 essential research questions must be answered before a vaccine can be achieved. The questions’ very basic nature—How much antigen should a vaccine contain? How many doses should be given? How long does vaccine protection last?—suggest how far flu-vaccine science has yet to go (see Bibliography: European Centre for Disease Prevention and Control 2007: Technical report).Funding: A starvation diet The historical low profile of flu research translated into a chronic lack of investment. For most of the past decade, as well as many years before that, the field was starved for money. In 2001—after the 1997 outbreak, but before H5N1 began its global spread—the NIH’s entire flu-research budget was $20.6 million, with $14.9 million of that in NIAID activities (see Bibliography: NIAID 2007). Funding stayed stagnant until the White House issued the National Strategy for Pandemic Influenza in November 2005 and called for $7.1 billion to be appropriated for flu. As of February, when the fiscal year 2007 budget was finalized, $5.3 billion had been appropriated overall, and NIH’s flu research budget had been raised to $222 million (see Bibliography: NIH 2007).Those appropriations have gone to fund a wide array of pandemic-preparation tasks, from improving state and local planning to supporting antiviral research (see Bibliography: Trust for America’s Health 2007). Strictly within the vaccine realm, funds have been divided among research, production, and purchase of existing vaccines for the national stockpile. As of May 2007, Congress had given the Department of Health and Human Services (HHS) $5.6 billion for pandemic preparedness; HHS has allocated $3.2 billion of that to expanding vaccine capacity. So far the agency has committed $1.5 billion of those funds, including $1 billion for research into alternative production methods such as cell culture, $147 million for research on low-dose vaccines, and $133 million for retrofitting existing plants to improve manufacturing capacity (see Bibliography: HHS 2007; Trust for America’s Health 2007).”We are finally starting to do the right thing, because money is being put in,” Poland said, “but we are late. We are really playing catch-up” (see Bibliography: Poland 2007).For the two years since federal money began flowing, scientific and public health groups have begged the administration to allocate more. In November 2005, May 2006, and again in April and June 2007, the Working Group on Pandemic Influenza Preparedness—an umbrella organization for 15 medical and science societies—unsuccessfully urged members of Congress to increase funding for the whole panoply of pandemic preparation, including vaccine research and development (see Bibliography: Working Group for Pandemic Influenza Preparedness 2005, 2006, 2007).US leads other countriesLate though the United States may have been in funding vaccine research, it nonetheless outshines other countries. “Government officials in the five Western European countries where influenza vaccine production facilities are located . . . have provided virtually no public funding to support H5N1 vaccine trials,” David Fedson, MD, wrote this summer in the Journal of Public Health Policy. “Germany is the sole exception, providing modest support for a trial of one company’s vaccine” (see Bibliography: Fedson and Dunnill 2007: Commentary). Fedson is a retired academic and vaccine-industry executive who has published critical analyses of pandemic-vaccine planning in a number of journals.There is widespread fear in the research community that the money is simply not enough.”The political inertia is surprising, particularly as politicians, if and when a pandemic eventuates, will be asked why, despite repeated warnings, they did not take appropriate action in time,” Lars Haaheim of the University of Bergen said in a stinging May article in Influenza and Other Respiratory Diseases. “With very few exceptions, the academia, research establishments and vaccine industry [have] had to settle for meagre and sometimes no public support at all” (see Bibliography: Haaheim 2007).Back to top Part 2: Vaccine production capacity falls far shortThe difficult reality is that, even if influenza science were perfect and research funding were abundant, achieving a widely deployable pandemic vaccine is currently out of reach. Chief among the reasons: The world lacks the manufacturing capacity to make enough vaccine to matter.Food and Drug Administration (FDA) planners have accepted that, absent rapid changes in current flu-vaccine manufacturing techniques, delivering the earliest doses of a vaccine tuned to a newly emerged pandemic strain would take a minimum of 4 months (see Bibliography: Goodman 2006). A vaccine-industry scenario, described in August in the journal BioPharm International, goes out 6 months: 3 to 4 months to generate a seed strain, 4 to 6 weeks of manufacturing set-up, and 18 weeks of production, including 2 to 3 weeks of quality assurance and regulatory approval—all adding up to a vaccine product that would arrive roughly in time for the pandemic’s second wave but long after the first patients had recovered or died (see Bibliography: Thomas 2007).But the more difficult obstacle is not the time needed to produce vaccine—which newer technologies such as cell culture could shorten to some degree—but the amount of vaccine needed. Despite years of work, the grave mismatch between predicted demand and likely supply has yet to be solved.The World Health Organization’s (WHO’s) own best-case analysis, published in the agency’s 2006 “Global Pandemic Influenza Action Plan to Increase Vaccine Supply,” and updated in an Oct. 23, 2007, press release,breaks down the situation this way. In 2006,global manufacturing capacity for seasonal flu vaccine was 350 million doses per year of trivalent vaccine (comprising one 15-microgram [mcg] dose of each ofthree flu strains’ antigens). This year, according to the WHO, capacity could rise as high as 565 million doses, a total that incorporates both actual capacity increases achieved by manufacturers and theoretical capacity that would be created if manufacturing lines ran around the clock for the entire calendar year—something they do not do for seasonal flu-vaccine production. Given that a pandemic vaccine would be aimed at a single strain rather than three, global capacity could thusrise as high as 1.5 billion doses. But a pandemic vaccine would need to be given twice, because, unlike with seasonal flu, there would have been no prior exposure to the novel strain. So absent the use of adjuvants to stretch limited antigen supplies, industry could produce at best enough vaccine for 750 million people, far short of the amount needed to cover the world’s 6.7 billion inhabitants (see Bibliography: WHO 2006: Global influenza action plan; WHO 2007: Projected supply of pandemic influenza vaccine; Palkonyay 2007).A vaccine embargo?The WHO analysis hides a number of highly optimistic assumptions, including zero glitches in production and 100% cooperation by regulators. But the greatest assumption may be that the newly produced pandemic vaccine would be distributed equitably to all comers around the globe. It is more likely that vaccine would never leave the countries where it is produced.Seven hundred and fifty million “is fewer than the number of people that live in the nine countries that produce 85% of the world’s supply of flu vaccine,” said David Fedson, MD, a retired academic and vaccine-industry executive who has published critical analyses of pandemic-vaccine planning. “Which means that, if you live outside of a vaccine-producing country—whether that means Indonesia or Sweden or Spain—you get nothing” (see Bibliography: Fedson 2007: Author interview).The nine countries—France, Germany, Italy, The Netherlands, Switzerland, the United Kingdom, the United States, Canada, and Australia—trade vaccine across borders but are unlikely to keep doing so in a pandemic, he added: “In 2000, a total of six western European companies distributed 66 million doses of vaccine to 18 western European countries. Only 42% of these doses were distributed within the countries that produced them; the remaining 58% were exported to other western European countries. For the rest of the world, about 40% of the doses used in central and eastern Europe, 60% of the doses used in the western Pacific and Southeast Asia, and virtually 100% of the doses used in Latin America, the eastern Mediterranean, and Africa were imported from one or more of the nine vaccine-producing developed countries”(see Bibliography: Fedson 2003).In one example of the supply-demand mismatch, the United States plans to secure enough pandemic vaccine to deliver two doses to all 300 million of its residents (see Bibliography: FDA 2007: Committee meeting transcript). But current US manufacturing capacity tops out at 150 million 15-mcg doses, a total that is expected to rise to 250 million when a new Sanofi Pasteur plant comes online in 2008 (see Bibliography: Sanofi Pasteur 2007), but that still falls far short of the number the federal government hopes to deploy. And those hoped-for 600 million doses do not include the 40 million destined for the US pandemic stockpile that must be replaced periodically as flu strains mutate or the vaccine expires (see Bibliography: Riley 2007).The role of seasonal flu vaccine demandThe WHO action plan avers that manufacturers will significantly expand production capacity by 2012, largely because demand for seasonal flu vaccine will rise—but it offers no evidence that demand can be stimulated to levels that will persuade manufacturers to invest (see Bibliography: WHO 2006: Global pandemic influenza action plan). In the United States, for instance, the amount of vaccine manufactured has risen nearly every year, but so too has the amount returned to manufacturers unused. In the 2006-07 season, manufacturers selling to the US market delivered 120.9 million doses, the highest on record; they received back 18.4 million unused doses, also a record (see Bibliography: Santoli 2007).The WHO plan asks countries that do not now use seasonal flu vaccine to launch new seasonal vaccination campaigns as a way of stimulating demand. It also asks countries with existing vaccination programs to increase vaccine use, so that 75% of those for whom vaccination is recommended are taking the shot. Both recommendations may be unrealistic: The United States, which uses more vaccine than any other nation, has never reached 75% uptake even among groups that are urged to take the shot because they are at high risk for flu complications. In the 2005-06 flu season, according to CDC data published in September, the highest acceptance of seasonal flu shots—69.3%—was among adults older than 64, who are considered “high risk” because of their age. Fifty- to 64-year-olds who are at high risk because of chronic medical conditions had a vaccination rate of 48.4%; only 32.3% of those in the same age range who had no high-risk conditions took the flu shot, and only 18.3% of healthy adults between 18 and 50 did so (see Bibliography: CDC 2007).”I have never believed that boosting seasonal flu-vaccine demand was the way to prepare for pandemic flu,” said Michael Osterholm, PhD, MPH, director of the University of Minnesota Center for Infectious Disease Research and Policy (CIDRAP), which publishes CIDRAP News, and of the National Institutes of Health (NIH)–funded Minnesota Center of Excellence for Influenza Research and Surveillance. “That economic model doesn’t work on its own and it has no scalability to provide flu vaccine for the rest of the world” (see Bibliography: Osterholm 2007).Little incentive to buildMany experts have warned that the only way to expand flu-vaccine manufacturing capacity is to get governments to pay for it. In its 2004 “Consultation on priority public health interventions before and during an influenza pandemic,” the WHO cautioned: “Industry has little incentive to build additional manufacturing capacity, which requires very large long-term investments for an event that occurs only rarely and unpredictably.” (See Bibliography: WHO 2004) Last year, Britain’s Royal Society added bluntly: “It is not commercially viable for the vaccine industry to commit the necessary resources to scale up production in advance of a pandemic when there is no existing market, the threat of a pandemic may be years away and the risk in any single year may be considered to be low” (see Bibliography: Royal Society 2006).Creating enough vaccine-manufacturing capacity to protect the world’s population is not cheap. The price tag is likely to be at least $2 billion and could rise to $9 billion, according to a WHO estimate (see Bibliography: WHO 2006: Global pandemic influenza action plan). Experts within the vaccine industry say that expecting manufacturers to make the investment asks companies to spend against their own best interest. “In the US market alone by the year 2010 there could be a surplus capacity resulting from ‘building for demand’ for pandemic preparedness but ‘suboptimal utilization’ based on significantly lesser demand for seasonal vaccines,” an engineer and two strategists from the Danish biotech firm NNE PharmaPlan wrote in the industry journal BioPharm International. “In Europe, Asia and the rest of the world, planned future capacities for ‘pandemic preparedness’ would have to address how potential surplus capacities can be effectively used in markets where there is little or no demand for seasonal vaccines” (see Bibliography: Thomas 2007).The United States has already experienced the aftermath of vaccine companies’ feeling overextended. Between 1998 and 2002, two of the four companies that then supplied seasonal flu vaccine left the market, citing losses on investment and increased regulatory demands. In the 2000-01 and 2003-04 flu seasons, the country experienced significant shortages of flu vaccine, with long lines, panic buying, price-gouging, and subsequent congressional investigations (see Bibliography: GAO 2001, 2004; Grady 2004).The same scenario could happen again. “The U.S. will have a serious problem if the pandemic doesn’t strike in the next couple of years, because interest will decline and demand will go down again,” said Hedwig Kresse, an associate analyst for infectious diseases with the British-based market analysts Datamonitor. “Governments will have to guarantee a certain sales volume to keep [manufacturers] in the market and to keep these capacities up” (see Bibliography: Kresse 2007).While the US government has taken initial steps to support manufacturers—witness the $133 million given to two manufacturers this past summer to retrofit existing plants and the $1 billion awarded for cell-culture research—much more is needed (see Bibliography: HHS 2006, 2007).”If we really want to have surge capacity for pandemic vaccine, we have to invest in it like we do our oil reserves, or military reserve capacity,” Osterholm said. “The facilities may sit for years before they are utilized. But the analogy is having an airport fire department in case of a plane crash: You hope never to use it, but you invest as though it were a possibility” (see Bibliography: Osterholm 2007).To be useful, those investments must be made well in advance of when vaccine is needed: The WHO estimates that building and licensing a new vaccine production line takes up to 5 years (see Bibliography: WHO 2004).What about vials and syringes? While vaccine manufacturers are likely grateful for the HHS funding, others in the industry say the investment is incomplete—because it does nothing to expand capacity for critical downstream tasks such as bottling and administering completed vaccine.The “fill-finish” sector—which puts bulk manufactured vaccine into vials or syringes—is not being asked to prepare for any excess capacity, said Jack Lysfjord, vice-president for pharmaceutical consulting in the Valicare division of Robert Bosch Packaging Technology Inc., in Brooklyn Park, Minn., a leading manufacturer of production and fill-finish equipment. “We are talking to some companies, but we are not hearing that they plan to buy twice as much from us in the next five years,” he said. “If they want to expand, they should be starting production now” because building an automated filling line can take 2 years (see Bibliography: Bosch 2007).The same frustration is evident at BD (formerly Becton, Dickinson and Co.), the dominant company in syringe manufacturing.”Everyone understands that if you don’t have vaccine you are dead in the water, but what has not been dealt with is that, if you don’t have the syringes and needles, the vaccine doesn’t do you any good,” said George Goldman, senior director for hypodermics at BD Medical Surgical Systems in Franklin Lakes, N.J. “Six hundred million devices, which is what in theory would be required to vaccinate the US population twice, is a very large volume if you plan for it and an even larger volume if you produce them in a reactive mode. We do not believe the industry is capable of producing that kind of volume in any short period of time under the best of circumstances” (see Bibliography: BD 2007).Manufacturing 600 million syringes would take 2 years if manufacturers used only their existing excess capacity, Goldman said, and creating a new manufacturing line takes approximately a year.”We have been working at the federal, state, even the local level to try to make sure this issue is visible,” he said. “To date, the results have been underwhelming.”The companies that occupy the end of the vaccine-production process are also experiencing anxiety—on their own behalf and for the pharmaceutical manufacturers who feed product to them—that their operations will be disrupted by the start of a pandemic if they are brought into the process too late.As a foreign-owned company, with its US unit in Minnesota andheadquarters and manufacturing plants in Europe, Bosch feels this acutely. Much of the fill-finish equipment sold out of its US plant undergoes preliminary assembly in Germany, and many of the manufacturers for whom Bosch makes equipment rely on pharmaceutical ingredients or production components sourced from around the world.”You have to think about every part of the components,” Lysfjord said. “The machines, the plants, the chemicals; the stopper, the glass, the aluminum overcast for the top of the vial; the labels. You’re not aware of how well-connected the system is until it breaks, and it is going to break big-time.”Back to top Part 3: H5N1 poses major immunologic challengesMany of the difficulties facing achievement of a pandemic influenza vaccine could not have been anticipated before the pandemic threat arose: They are intrinsic to the H5N1 virus itself.Some are obvious. Because all flu viruses mutate rapidly, antigenic drift and division into clades, or subgroups, has already rendered some early vaccine candidates less potent against circulating strains (see Bibliography: Smith 2006, Riley 2007). Because this flu virus is highly pathogenic, it must be handled initially in one of a relatively small number of high-biosecurity laboratories (see Bibliography: WHO 2004) and also requires the use of reverse genetics to create a seed strain that will reproduce in eggs. Reverse genetics and the stringent pre-release testing that follows add a minimum of 6 weeks to the vaccine production process (see Bibliography: Wood 2007: Reference viruses). And absent regulatory changes, the resulting seed strain could be considered a genetically modified organism under European Union rules or a select agent under US law, further restricting the laboratories, personnel, and manufacturers who could work with it from then on (see Bibliography: Stephenson 2006: Development and evaluation).Reverse genetics may be responsible for a phenomenon noted by several researchers: H5N1 does not reproduce well in vitro, a potentially major obstacle for vaccine production because it would greatly lengthen the manufacturing timeline. “Most manufacturers report that yields of antigen from reverse genetics–derived H5N1 viruses are 30-40% of the average of seasonal influenza viruses, reducing the quantity of antigen available for vaccine formulation,” Iain Stephenson of University Hospital-Leicester and colleagues wrote last year in Lancet Infectious Diseases (see Bibliography: Stephenson 2006: Development of vaccines).Vaccines show poor immunogenicityFurthermore, when candidate vaccines have been produced from them, H5N1 and similar viruses have not done a good job of provoking an immune response. This was noted as early as 1998, when an early attempt to create a vaccine in the wake of the 1997 Hong Kong outbreak used an antigenically similar H5N3 strain—only to find it was poorly immunogenic even at the highest concentration of two 30-microgram (mcg) doses (see Bibliography: Nicholson 2001). There were similarly poor results in 2006 and 2007 trials that used an H5N1 strain isolated from Vietnam in 2004 and modified by reverse genetics (see Bibliography: Bresson 2006, Leroux-Roels 2007): Even at the highest dosage given (two 30-mcg doses), neither trial induced levels of immune protection that would be acceptable to the Food and Drug Administration (FDA) or the European Union’s Committee for Medicinal Products for Human Use (CHMP).But the best example of H5N1’s poor immunogenicity is the 2006 trial that led to the first FDA licensing of an H5N1 vaccine. The trial, which used the same modified 2004 Vietnam strain as the others, achieved acceptable levels of protection only at the highest amounts given, two doses of 90 mcg each, or 12 times the 15-mcg dose that induces immunity in a seasonal vaccine (see Bibliography: Treanor 2006: Safety and immunogenicity of an inactivated subvirion influenza A [H5N1] vaccine). Even at that dosage, only 54% or 58% of the subjects (by two different measures) exhibited antibody titers that matched FDA and CHMP regulations, compared with the 70% to 90% usually achieved with seasonal vaccine (see Bibliography: CDC 2005).The trial’s investigators acknowledged that the extraordinarily high dose necessary to protect was an unsatisfying result, saying, “The need for a vaccine with a total dose of 180 mcg would pose a considerable barrier to rapid production of a supply that would be adequate to meet the world’s requirements should a pandemic occur” (see Bibliography: Treanor 2006: Safety and immunogenicity). Experts who reviewed the data during FDA deliberations on licensure agreed, signaling that they hoped for improved results as research advances. “There are numerous vaccines under development that are potentially better, if you will, than this vaccine. This is an interim vaccine,” Norman Baylor, PhD, director of the FDA’s Office of Vaccines Research and Review, said during the FDA hearing (see Bibliography: FDA 2007: Committee meeting transcript).The amount of antigen needed in that vaccine concerns researchers several times over. It is so high that the vaccine would stress the manufacturing system if put into broad production, although regulators at the licensure hearings said the vaccine is intended only for federal stockpiling and not for commercial sale. In addition, they fear the high dose—which at 180 mcg total is four times the total seasonal trivalent dose—could provoke an unusual rate of adverse reactions (see Bibliography: FDA 2007: Committee meeting transcript).(Regulators may be quietly bracing for adverse publicity as well. Testimony at the same FDA committee meeting indicated that, because of limitations on fill/finish capacity, the 90-mcg vaccine being manufactured for the US stockpile will be packaged in multi-dose vials which, to guard against contamination, will contain the still-controversial preservative thimerosal.)Immunity hard to measureThe 2006 trial’s unsatisfying results highlighted a chronic concern in flu-vaccine research: the lack of reliable correlates of immunity for pandemic vaccines. Given the lack of a vaccine, moderate antiviral resistance, and a case-fatality rate of more than 60%, humans cannot ethically be experimentally exposed to the H5N1 virus. Yet none of the animal models—mice, ferrets, or the recently proposed guinea pigs (see Bibliography: Lowen 2006)—is a perfect substitute. Hence the research community relies instead on measures of human antibody response that are neither uniform across laboratories nor universally agreed to by regulatory bodies.”I think this is our biggest scientific issue—that we are not sure what the appropriate surrogate for protection is, given the fact we have no ability to challenge [expose humans] and are not likely to,” said flu epidemiologist Dr. Arnold Monto of the University of Michigan (see Bibliography: Monto 2007).In the United States, the FDA-accepted surrogate for immunity in flu-vaccine trials is a hemagglutination-inhibition (HI) antibody assay that returns a post-vaccination titer of more than 1:40 for 70% of those vaccinated (see Bibliography: FDA 2007: Guidance for industry: clinical data needed to support the licensure of seasonal inactivated influenza vaccines). But that measure is known to be imperfect even for seasonal flu: Patients with higher titers have contracted flu, while those with lower post-vaccination titers have apparently been protected (see Bibliography: Poland 2006). Additionally, the HI test appears in the lab to be less sensitive to H5 antibodies than it is to the seasonal strains H1 and H3; a second test, virus microneutralization, appears more sensitive but also has no agreed-upon clinical correlates (see Bibliography: Stephenson 2004). Researchers have resorted to using a 1:40 result as the best available measure of immunologic response, while conceding that it may not indicate actual degrees of protection.”It’s important to understand that this choice of a 1:40 endpoint is not validated in any way as an actual assessment of protection against H5 in humans,” Dr. John Treanor of the University of Rochester, principal investigator for the trial that produced the licensed H5 vaccine, said at the FDA licensure hearings. “It might be just as valid to choose a 1:20 or a 1:80 or a 1:10 endpoint. But it’s really more a convenient way in order to discriminate responses between groups” (see Bibliography: FDA 2007: Committee meeting transcript).Unfortunately, HI titer results vary wildly. In two studies, European labs performing the same test for seasonal flu strains returned results that varied from 16- to 128-fold, and for H5N1, labs have achieved different results depending on the source and age of the animal cells used in the assay (see Bibliography: Wood 2007: International standards). The WHO is pursuing international agreement on a standard for H5N1 tests, similar to standards achieved earlier for measles, polio, rubella, and other infectious diseases.But the problem with finding correlates of immunity goes further. The HI test may not return reliable results for vaccines that provoke types of immunity other than antibody response. That makes it an unreliable measure for the effectiveness of two promising alternative classes of vaccines: live-attenuated vaccines, which have the potential to generate immunity against multiple strains of flu, and inactivated adjuvanted vaccines (those containing a chemical immune-system stimulant), which could help solve the supply bottleneck by allowing much smaller amounts of antigen to be dispensed in each vaccine dose (see Bibliography: Subbarao 2007, Wood 2007: Author interview).Back to top Part 4: The promise and problems of adjuvantsAdjuvanted vaccines appear to hold the greatest promise for solving the grave supply-demand imbalance in pandemic influenza vaccine development. They come with obstacles—immunologic, regulatory, and commercial—but they also have generated more excitement than any other type of vaccine thus far.In an example of the hope being hung on adjuvants, the WHO last week issued a statement declaring that the pandemic vaccine supply is “sharply” increasing and forecasting that annual manufacturing capacity will rise to 4.5 billion two-dose courses by 2010 (see Bibliography: WHO 2007: Projected supply). The forecast is based on the expectation that flu vaccines made in 2010 will include an adjuvant permitting the use of just one-eighth of current vaccines’ antigen content. (Adjuvants are chemicals that are incorporated in some vaccines to improveresponse to the vaccines’ active ingredient. Adjuvants make it possible to reduce the dose of antigen in a vaccine without dampening the immune response.)”We have H5N1 to thank for opening up the flu research field, which was absolutely creeping along,” said Dr. Arnold Monto, a flu epidemiologist at the University of Michigan, who has long research experience with live-attenuated vaccine. “We’ve always known that flu vaccine was good, but not great—not a 21st century vaccine with 95% protection—but there was a feeling that it was good enough. But H5N1 changed the risk-benefit ratio so that we are willing for instance to work with adjuvants, which may have theoretical risks but certainly may well afford tangible benefits. We’re going to learn a whole lot about the immunology of protection that we haven’t learned in the past” (see Bibliography: Monto 2007).While adjuvants hold the greatest promise for dose-sparing, they also provoke trepidation because they are by definition immune-system activators.While many have been tested over the years, few have entered the market, because they proved too reactogenic to be acceptable to consumers or safe. Only one set of adjuvants, aluminum salts or alum (aluminum hydroxide, aluminum phosphate, and potassium aluminum sulfate), is licensed in the United States. Aluminum adjuvants and MF59, an oil-in-water emulsion that contains squalene (an oil found in some fish oils), are licensed in Europe (see Bibliography: Petrovsky 2007).No adjuvanted flu vaccine is licensed in the United States—a notable oversight since federal health authorities urged such a vaccine be investigated as a preparedness measure after the pandemic of 1957 (see Bibliography: Strikas 2005). Fifty years later, the need to seek regulatory approval for novel components in adjuvanted pandemic vaccines could prove a barrier to rapid market entry of formulas that look promising.Adjuvants old and newEarly hopes for an adjuvanted H5N1 vaccine focused on alum, because it is well-understood and widely licensed, but those formulas have proved disappointing. A phase 1 study of alum-adjuvanted vaccine made by the Chinese company Sinovac Biotech achieved acceptable levels of protection using two doses of only 10 micrograms (mcg) of flu antigen—but that formula was based on an inactivated whole virus, a flu-vaccine type that is licensed in the European Union but not currently used in the United States (see Bibliography: Lin 2006).Two other alum-adjuvanted vaccines that used whole viruseshave shown some promise for antigen sparing. At a February 2007World Health Organization (WHO) meeting, Norbert Hehme of GlaxoSmithKline Biologicals reported that a regimen of two 15-mcg doses met EU criteria for immune response (see Bibliography: Hehme 2007). And in May, Hungarian investigators reported that they had achieved an acceptable immune response in a small study using a formula (based on a seasonal vaccine already licensed in the EU) containing a single dose of only 6 mcg (see Bibliography: Vajo 2007). Two alum-adjuvanted vaccines that used the split-virus formulation common in the United States have reported levels of immune response acceptable to regulators at two doses of 45 mcg (see Bibliography: Keitel 2007) or 30 mcg (see Bibliography: Bresson 2006). But those levels of antigen are so high that deployment of those vaccines would not allow significant dose-sparing.The most provocative news in dose-sparing has come in the past several months. In August, scientists working with a GlaxoSmithKline formula published a trial of a two-dose regimen of an inactivated split-virus vaccine adjuvanted with a proprietary oil-in-water emulsion; after the second injection, even the lowest dose of 3.8 mcg exceeded EU criteria for immune response (see Bibliography: Leroux-Roels 2007). And in September, Sanofi Pasteur reported in a press release that an inactivated vaccine adjuvanted with the company’s own proprietary formula induced EU-accepted levels of protection after two doses of 1.9 mcg.Regulatory barriers loomLike many other aspects of pandemic planning, adjuvants’ ability to solve some of the challenges of preparedness will depend on how rapidly a pandemic arrives. That is because the most promising vaccines rely on formulas that have not yet been licensed in the United States. The Food and Drug Administration (FDA) has indicated that pandemic vaccines made in the same manner as an already-licensed seasonal vaccine may be treated only as a “strain change,” in an accelerated approval process by which components are swapped out of existing seasonal flu vaccines each spring. But since there are no adjuvanted seasonal flu vaccines currently licensed in the United States, antigen-sparing pandemic vaccines may require a full Biologics License Application—the complete portfolio of testing and data, on both the product and the manufacturing facility, that is demanded of any new drug submitted for licensure and can take years to assemble (see Bibliography: FDA 2007: Guidance for industry: clinical data needed to support the licensure of pandemic influenza vaccines).Moreover, at the moment both the FDA and the European Union’s drug agency consider adjuvants to be a component of vaccines, not a product separate from vaccines—implying that adjuvants can be brought forward only as part of a precise antigen dose/adjuvant combination that must be tested for safety and efficacy, probably in a “non-inferiority” trial against the same antigen dose without adjuvant, and then submitted for licensure (see Bibliography: European Agency for the Evaluation of Medicinal Products 2005; FDA 2007: Guidance for industry: clinical data needed to support the licensure of seasonal inactivated influenza vaccines).”We have not taken the position that an adjuvant can be thought of as a stand-alone product,” Dr. Pamela MacInnes of the National Institutes of Health said at an FDA advisory committee meeting last February. “It’s a product that has antigen in combination with an adjuvant that comes forward for licensure” (see Bibliography: FDA 2007: Committee meeting transcript).Mixing and matchingThere is currently no regulatory pathway by which adjuvants may be submitted for approval as products by themselves—or may be paired with a separately manufactured antigen, perhaps one produced by another company. Regulators acknowledge that could stand in the way of, for instance, converting the already-manufactured vaccine in the national stockpile (which was purchased under the 90-mcg-dose license granted Sanofi Pasteur earlier this year but is held in bulk) to an adjuvanted vaccine that could be stretched much further.”There probably are more concerns about an antigen made with one manufacturing process and an antigen made with another manufacturing process and whether when those are mixed with ideal adjuvant X in two potentially different circumstances or time points, that could raise a bunch of issues about formulation, stability, immunogenicity, safety,” Dr. Jesse Goodman, director of the FDA’s Center for Biologics Evaluation and Research, said at the FDA meeting (see Bibliography: FDA 2007: Committee meeting transcript).The US Department of Health and Human Services (HHS) issued $132.5 million in contracts in January 2007 to three companies—GlaxoSmithKline, Iomai, and Novartis—to study antigen technology, including the possibility of mixing and matching adjuvants with separately manufactured antigens (see Bibliography: GSK 2007; Iomai 2007; Novartis 2007: Novartis receives US government contract). Manufacturers have welcomed the government interest because negotiating combinations of components from different companies is fraught with antitrust and intellectual-property pitfalls.”I have heard a lot of people say they expect problems with adjuvanted vaccines,” said Hedwig Kresse, an associate analyst for infectious diseases with the British-based market analysts Datamonitor. “It is a technology that definitely has some potential, but there are a lot of issues that need to be addressed first” (see Bibliography: Kresse 2007).Back to top Part 5: What role for prepandemic vaccination?Experiments with vaccine adjuvants have raised some hope of removing one of the great stumbling blocks to pandemic influenza preparedness: the impossibility of making a vaccine that protects against a pandemic virus before that virus actually emerges.A number of the studies that have shown adjuvants may be able to stretch the vaccine supply also demonstrated a secondary benefit: The formulas protected not only against the H5N1 flu strain on which they were based, but against other H5N1 strains as well, a phenomenon called cross-reactive protection (see Bibliography: Nicholson2001, Stephenson 2005, Govorkova 2006, Hehme 2007, Hoffenbach 2007). Most recently, the GlaxoSmithKline-backed team that described an acceptable immune response after two adjuvanted 3.8-microgram (mcg) doses found that three fourths of their subjects were protected not only against the clade 1 Vietnam virus on which the vaccine was based, but against a drifted clade 2 virus from Indonesia as well (see Bibliography: Leroux-Roels 2007).The findings are not completely understood, though researchers agree that they make biological sense. Adjuvants stimulate the immune system in some manner that is broader than and different from the body’s reaction to the antigen packaged with them. The discovery that adjuvanted flu vaccines may invoke cross-reactivity has generated tremendous excitement—because that could allow production of at least partially protective vaccines well in advance of a pandemic’s beginning.A tough ethical problemBut the next logical step—that if vaccines can be formulated without waiting for a pandemic, they could be administered before a pandemic began—is a much tougher one to take, and policy makers are approaching it with great caution.The scientific, logistical, and especially ethical questions raised by prepandemic vaccination are grave.Any vaccination that took place before a pandemic was detected would offer uncertain amounts of both benefit and risk. The vaccine might be cross-protective against a future pandemic—but the lag time to the pandemic’s emergence might be so long that the vaccination would seem pointless. As well, the vaccine might cause a greater-than-expected rate of adverse events, causing both direct harm to recipients and indirect damage to government credibility—results that would be particularly difficult to tolerate if vaccination proved unnecessary because the pandemic did not arrive. Those risks are not theoretical: They have been demonstrated in the United States twice in recent history, in the abortive 2002 smallpox vaccination campaign and the 1976 swine-flu campaign (see Bibliography: Kotalik 2005), which has haunted US flu decision-making ever since.The danger demonstrated by both those campaigns, of causing adverse events while protecting against a disease that might never arise, has been noted in World Health Organization (WHO) policies as well. “Possible high-risk shortcuts in response to a potential emergency would be difficult to justify prior to the actual occurrence of the emergency,” the agency said after the June 2006 meeting of its Global Advisory Committee on Vaccine Safety. “Effectiveness of pandemic vaccines will not be known before the pandemic and possibly only after it is over” (see Bibliography: WHO 2006: Global Advisory Committee on Vaccine Safety, 6-7 June 2006).Yet the potential benefits of prepandemic vaccination are so alluring that governments have begun gingerly to lay groundwork for its consideration, despite the obvious difficulties of putting the idea into practice.”Extraordinary threats call for consideration of innovative strategies that, in less-threatening circumstances, might be dismissed,” Bruce Gellin and Ben Schwartz of the Department of Health and Human Services’ National Vaccine Program Office wrote 2 years ago. “Although it has been assumed that pandemic vaccine cannot be stockpiled or that vaccination cannot occur before the start of a pandemic, might these approaches actually be possible? . . . Would receipt of a vaccine prepared before the pandemic be effective in providing some protection or in priming recipients so a single subsequent dose of vaccine would be protective?” (see Bibliography: Schwartz 2005).The prime-boost strategyThe most likely and biologically plausible use of prepandemic vaccination would be as the first half of a “prime-boost” series. People would still be given the two doses of vaccine necessary to provoke immunity in a naïve individual. But the doses would be based on different vaccine strains—the first an early best guess, the second tuned to the pandemic strain—and could be given not weeks but months or years apart if the science supported it.At the moment, however, the science is thin. Much of the support for priming has come from animal studies (see Bibliography: Lipatov 2005, Govorkova 2006, Kreijtz 2007) or via computer modeling (see Bibliography: Longini 2005, Ferguson 2006, Germann 2006). A few small studies in humans have shown promising results. In one, serum from 15 volunteers who received three doses over 16 months of an adjuvanted vaccine based on a 1997 H5N3 isolate showed significant antibody response against H5N1 strains isolated years later (see Bibliography: Stephenson 2005). In another, 37 participants who had been given a baculovirus-grown, clade 3 H5 vaccine in 1998 were boosted with a single dose of the unadjuvanted 90-mcg Sanofi vaccine in 2005, and showed much higher antibody responses than participants who had not been primed but received one or two doses of the 90-mcg vaccine (see Bibliography: Treanor 2007: Immune responses). And researchers at a conference earlier this year reported that some of the participants in the phase 3 trial of the 90-mcg Sanofi vaccine were boosted with a third dose 6 months after their second dose and showed a significant rise in antibody levels that lasted for 6 months (see Bibliography: Zangwill 2007).Hurdles are manySo many steps separate those early results from an agreed-upon policy that would allow for prepandemic vaccines—in an annual flu shot or stockpiled until the WHO declares a pandemic imminent—that it is unrealistic to expect them to be created any time soon. The scientific questions alone are significant and novel.”I think priming should be done, but I am not sure how it should be done,” said Dr. John Wood, principal scientist in the division of virology at the United Kingdom’s National Institute for Biological Standards and Control. “What we don’t know is how low you can go to actually prime people. It may be that you can go much lower than where we can detect antibody. That is a regulatory headache, because you have to demonstrate that you are doing something, but there is a potential there” (see Bibliography: Wood 2007: author interview).To achieve prepandemic vaccines, researchers would have to ascertain the right dose and dose interval, determine how long priming lasts, and solve the puzzle of measuring primed immunity. Further, regulatory authorities would have to determine the trial design that could deliver those answers, the public discussion that would be necessary for prepandemic vaccines to be accepted, and the safety data that would need to be gathered once the vaccines went into use (see Bibliography: Goodman 2007).Recognizing those hurdles, the European Centre for Disease Prevention and Control said in August that while it welcomes the development of prepandemic vaccines, it would not support administering them until a WHO declaration of pandemic phase 5 or 6, meaning significant human-to-human transmission is occurring or a pandemic is under way (see Bibliography: ECDC 2007: “Pre-pandemic” vaccines might offer protection but uncertainties remain).Back to top Part 6: Looking to novel vaccine technologiesFrustration with the slow pace of pandemic-vaccine achievement has spurred second looks at both old and new technologies, such as using whole influenza viruses instead of fragments or growing flu viruses in cultures of mammalian cells instead of in eggs.Such approaches may yield cross-protection against various H5N1 strains, shorten the production timeline, or increase the amount of vaccine that can be produced. As with the inactivated subvirion or split-virus vaccines, however, much of the research into new types of vaccines and forms of delivery is in its early stages, and the vaccines could be years away from marketability. Few of them pass the real-world tests specified recently by David Fedson, MD, in the Permanente Journal. Fedson, a retired vaccine-industry executive who has analyzed pandemic vaccine planning, wrote that the vaccines must be “scientifically promising,” they must be “licensed or near licensure,” and “the global industrial capacity to produce them must be large and already in place” (see Bibliography: Fedson 2007: New approaches).Among older and known technologies, the lure of cross-reactive protection has spurred a second look at inactivated whole-virus and live-attenuated flu vaccines. Some whole-virus trials have returned encouraging results. But in the past, whole-virus vaccines’ much higher rate of adverse reactions has kept them out of commercial use in the United States. As a result, “if whole-virus vaccines are confirmed to be more immunogenic than subvirion vaccines, this will pose challenges to manufacturers and regulators, since it will require substantial changes to existing licensed production processes,” Iain Stephenson of University Hospital-Leicester and colleagues observed in Lancet Infectious Diseases (see Bibliography: Stephenson 2006: Development of vaccines against influenza H5).Pros and cons of live vaccinesLive-attenuated vaccine has been the Cinderella of the seasonal flu vaccine world, struggling for market share since it was introduced in 2003 by MedImmune (now part of AstraZeneca). Even during flu-shot shortages, its acceptability was hampered by restrictive FDA indications limiting its use to 5- to 49-year-olds, as well as a formula that required physicians to keep it frozen (see Bibliography: Rosenwald 2007). The vaccine was relaunched this year with a new formula that requires only refrigeration, along with a broadened indication permitting use in children as young as 2 years old, backed by research showing that it protected young children better than a shot (see Bibliography: Belshe 2007).Because they contain live virus, live-attenuated vaccines provoke multiple types of immunity. In studies they have been shown to protect against both the strains from which vaccine candidates were derived and against drifted (slightly mutated) strains as well—characteristics that make them highly appealing to pandemic planners (see Bibliography: Belshe 2004). They also grow in eggs at a much higher volume than inactivated vaccines (see Bibliography: Monto 2007). But their live-virus content is responsible for the vaccines’ greatest potential danger: the possibility that they might lead to reassortment between the vaccine virus and circulating flu strains.”Although such an event may not be of concern in the face of widespread disease from a pandemic strain of influenza, it would clearly be an unfavorable outcome if the threatened pandemic did not materialize,” Catherine Luke and Kanta Subbarao of the National Institutes of Health (NIH) wrote last year. They called for clinical trials of live-attenuated pandemic vaccine candidates in which, to eliminate the risk of reassortment, participants would be kept in inpatient isolation. “The risk for reassortment must be carefully considered by public health authorities before a decision is made to introduce a live, attenuated vaccine in a threatened pandemic,” they stated (see Bibliography: Luke 2006).Alternate routesSome researchers have urged attention not to new vaccines, but to new methods of administering vaccines. Intradermal vaccination appears to provoke acceptable levels of immunity while using only 20% to 30% of the standard intramuscular dose—but the injection technique is more challenging and may not be feasible for mass vaccination programs that might use less-trained volunteers (see Bibliography: Haaheim 2007).In another novel suggestion, academics from the University of Hong Kong recommended recently that health authorities consider giving lower-than-planned doses of vaccine during a pandemic, arguing that vaccinating more people with a reduced dose could create a mass effect large enough to slow down spread of the disease (see Bibliography: Riley 2007). That approach too has drawbacks, Christophe Fraser of Imperial College London said in a commentary: “We must . . . consider whether anyone is ready for the potential consequences of deploying a suboptimal vaccine in an uncertain attempt to maximize our herd protection, with a possible reduction in the extent of protection of individuals” (see Bibliography: Fraser 2007).The promise of cell-culture productionThe simplest but in some ways most challenging proposals for addressing the slow development of pandemic vaccines are ones that directly address the shortfall in flu antigen by radically changing production techniques.Cell culture is a known technology that is used for vaccines such as inactivated polio vaccine, but in the United States it has never been applied to flu. Moving flu vaccine production from eggs to cell culture would simplify manufacturing in several key areas. It would free manufacturers from the necessity of procuring enough eggs up to a year in advance. By dispensing with eggs, it would eliminate the need for putting a pandemic virus through reverse genetics, shaving 4 to 6 weeks off vaccine production. And because the vaccine virus is grown in giant industrial fermenters, it could offer a vast increase in production capacity—but only if manufacturers or governments make significant capital investments (see Bibliography: GlaxoSmithKline 2005, Novartis 2006) or manufacturers quickly convert the 2.5 million liters of cell-culture capacity (see Bibliography: FDA 2007: Committee meeting transcript) in use around the world for other pharmaceutical products. Either method of creating additional capacity would require the approval of regulatory bodies such as the Food and Drug Administration (FDA) before production could begin, unless governments enacted some form of emergency release.But additional investment at least is beginning: The Department of Health and Human Services (HHS) awarded $97 million to one manufacturer in 2005 and just over $1 billion to five manufacturers in 2006 (see Bibliography: HHS 2006), and manufacturers Novartis and GlaxoSmithKline have both begun building cell-culture plants in the United States. The first cell-culture vaccine for seasonal flu, made by Novartis, was approved by European Union authorities in June (see Bibliography: Novartis 2007: Novartis gains European approval).A refinement of the cell-culture strategy involves isolating the flu virus’s hemagglutinin gene and using recombinant technology to express the hemagglutinin in insect cells grown in bioreactors. The main commercial proponent of this process, Protein Sciences Corp., claims it can halve the standard production timeline while delivering higher yields (see Bibliography: Lauerman 2007). The baculovirus-expressed recombinant product has been successfully tested for safety and immunogenicity (see Bibliography: Treanor, Schiff 2006; Treanor, Schiff 2007), and the company has said it plans to submit a trivalent, seasonal-flu version of the vaccine to the FDA for licensure before the end of 2007 (see Bibliography: Protein Sciences Corp. 2007). Submission of a recombinant pandemic vaccine would follow approval of the seasonal vaccine, chief operating officer Manon Cox said at an FDA hearing earlier this year (see Bibliography: FDA 2007: Committee meeting transcript).The Holy GrailThe Holy Grail of flu vaccine—and the object so far of the greatest wistfulness—is a universal vaccine. “The optimal long-term solution to pandemic vaccination is the development of a new influenza vaccine against an antigen that is present in all influenza subtypes and does not change,” Ben Schwartz and Bruce Gellin of HHS’s National Vaccine Program Office wrote in 2005 (see Bibliography: Schwartz 2005). So far, however, vaccines based on conserved regions of the virus such as the M2 protein have shown only the ability to reduce disease, not to prevent infection, and have been tested largely in animals, though one clinical trial in humans began last summer (see Bibliography: Acambis PLC 2007).Back to top Part 7: Time for a vaccine ‘Manhattan Project’?Although money for pandemic influenza vaccine research has begun to flow and results have picked up speed, there is widespread frustration that it all took so long.”If we are serious about a pandemic, we should assume it is going to be imminent and we should be prepared as if it is imminent—not 10, 15 years down the road, but imminent,” said David Fedson, MD, a retired vaccine industry executive who has published analyses of pandemic vaccine planning (see Bibliography: Fedson 2007: Author interview).A chorus of calls to actionCalls have come from across the political spectrum for a more aggressive, better-funded, tightly organized research effort. Former Senate Majority Leader William H. Frist (R-Tenn.) called in August 2005 for a “Manhattan Project for the 21st century” (see Bibliography: Frist 2005). In the same month, Michael T. Osterholm, PhD, MPH, director of the University of Minnesota Center for Infectious Disease Research and Policy, publisher of CIDRAP News, recommended the creation of “an international project to develop the ability to produce a vaccine for the entire global population within several months of the start of a pandemic [that would be] a top priority of the Group of Seven industrialized nations plus Russia (the G-8)” (see Bibliography: Osterholm 2005).Further, the nonprofit, nonpartisan advocacy group Trust for America’s Health recommended in October 2006 that governments create a “multinational pandemic vaccine research and development master program” (see Bibliography: Trust for America’s Health 2006), and the Infectious Diseases Society of America (IDSA) echoed that call in January 2007, recommending an appropriation of $2.8 billion in such a project’s first year (see Bibliography: IDSA 2007).”An effort on the scale of the Apollo space project is required,” the IDSA said.The Manhattan Project and the nuclear bombs that resulted from it are a sensitive subject to raise in a health crisis that demands international cooperation—particularly a health crisis centered in Asia, where the bombs were used.But implicit in the invocation of that all-out effort is a hunger for the power, funding, freedom from bureaucracy, and single-minded focus that its leaders enjoyed. The Manhattan Project was founded at emergency speed: The lag time between Albert Einstein’s famous letter advising President Franklin Roosevelt that nuclear fission might permit the creation of “extremely powerful bombs” and the first meeting of a newly formed federal Advisory Committee on Uranium was a mere 10 days. The project’s chief, Brigadier General Leslie Groves, was handpicked for his reputation for ruthless efficiency. Even after the United States entered World War II in December 1941, the project boasted the ability to cherry-pick any staff and claim any funding it needed; eventually it employed 130,000 people and received $2 billion in 1940s dollars (about $23 billion today).Most notably for parallels to pandemic policy, the Manhattan Project simultaneously pursued multiple research paths into nuclear fission and weapons development, dropping entire avenues of inquiry and increasing other labs’ funding and staff as results emerged. And from the time of Einstein’s letter in 1939 to the dropping of two atomic bombs on Japan in 1945, less than 6 years elapsed (see Bibliography: Schwartz 1998; Gosling 1999).”I feel as a scientist that we could make progress more rapidly if we sat down in advance and came up with a big-picture strategy and then funded it,” said Dr. Gregory Poland, director of the Mayo Clinic’s Vaccine Research Group in Rochester, Minn. “We have neither a process for rapidly developing new vaccines nor a track record” (see Bibliography: Poland 2007).The National Institute of Allergy and Infectious Diseases (NIAID), the primary conduit of federal flu research funds to scientists, believes it does have a robust research agenda. Dr. Carole Heilman, director of the division of microbiology and infectious diseases, points to the flu-research recommendations issued by a blue-ribbon NIAID panel this year as evidence that the agency is guiding extramural researchers to critical questions about flu (see Bibliography: Heilman 2007, NIAID 2007). But with funding limited until recently, much of the research being conducted came into being because of private-sector interests rather than an overarching plan, said longtime flu researcher Dr. Arnold Monto of the University of Michigan (see Bibliography: Monto 2007).Redefining the problemThose calling for a Manhattan Project–like effort say that what is needed is much broader than what NIAID or all of NIH could deliver. It requires active coordination among all the federal health agencies along with cooperation from congressional funders, plus parallel efforts in other countries. “Pandemic vaccine development has been viewed primarily as a vaccine problem that should be addressed with better science,” Fedson said, “but fundamentally it is a global public health problem that requires better management” (see Bibliography: Fedson and Dunnill 2007: From scarcity to abundance).And, they say, it is urgent that such an effort be established soon, because there is no way of predicting accurately when a pandemic might arrive. If it arrives soon rather than later, the lack of vaccine in most of the world will create a divide between haves and have-nots that could corrupt international relations long after the pandemic ends.The long standoff with the Indonesian government over sharing of H5N1 isolates has provided a foretaste of the disruption such resentment could cause. The health ministry of Indonesia—the country that has experienced the most human cases and deaths from H5N1 flu—stopped sending isolates to World Health Organization (WHO) collaborating laboratories in late 2006. Those laboratories both analyze the isolates to track the evolution of seasonal and novel flu strains and use them to develop pandemic vaccine candidates; Indonesia’s decision to stop contributing was apparently triggered by the realization that it could never afford to purchase vaccines made from isolates it provided.By challenging the WHO, Indonesia deprived the international community of a key source of information on emerging flu viruses. It also emboldened other developing countries to join its protest, leading to a week-long negotiation at the annual World Health Assembly (WHA), a WHA resolution promising reconsideration of the virus-sharing system, and WHO commitments to invest in vaccine manufacturing in the developing world. The concessions did not completely repair relations, however: The question of control over viruses remains open and will be discussed again at a WHO meeting in Geneva that opens Nov 5 (see Bibliography: McKenna 2007: System for global; McKenna 2007: Virus ownership).It is possible that failing to achieve a pandemic vaccine when it is needed—or even failing to confront in advance the possibility that supplies will fall short—could fracture international pandemic preparations just when cooperation will be essential.”At this point, when a pandemic happens, vaccines are going to provide some benefit to a very limited number of people,” Osterholm said. “But they are also going to create a major diversion of activity and energy when the decisions have to be made about who gets what limited vaccine exists. 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Flu vaccine: steps are needed to better prepare for possible future shortages. Testimony by Janet Heinrich before US Senate Special Committee on Aging. GAO-01-786T. May 30, 2001 [Full text]GAO. Flu vaccine: supply problems heighten need to ensure access for high-risk people. Report to Congressional Requestors. GAO-01-624. May 15, 2001 [Full text]Germann TC, Kadau K, Longini IR, et al. Mitigation strategies for pandemic influenza in the United States. Proc Natl Acad Sci 2006 Apr 11;103(15):5935-40 [Abstract]Goodman J. Considerations in the pre- and early pandemic use of influenza vaccine. Presented at FDA Center for Biologics Evaluation and Research Vaccines and Related Biological Products Advisory Committee Meeting, Gaithersburg, MD, Feb 27, 2007Goodman J. How fast can a new vaccine for an emerging respiratory virus be developed and available for use? Presented at the International Conference on Emerging Infectious Diseases, Atlanta, GA, Mar 22, 2006Gosling FG. The Manhattan Project: making the atomic bomb. Oak Ridge, TN: US Department of Energy History Division, Jan 1999Govorkova EA, Webby RJ, Humberd J, et al. Immunization with reverse-genetics–produced H5N1 influenza vaccine protects ferrets against homologous and heterologous challenge. J Infect Dis 2006 Jul 15;194(2):159-67 [Full text]Grady D. With few suppliers of flu shots, shortage was long in making. New York Times. Oct 17, 2004 [Full text]GSK (GlaxoSmithKline). Backgrounder: Egg-based vs. cell-based influenza vaccine production. 2005GSK. GlaxoSmithKline awarded $63 million HHS contract for pandemic vaccine research and development. Jan 17, 2007 [Press release]Haaheim L. Vaccines for an influenza pandemic: scientific and political challenges. Influenza Other Respir Virus 2007;1(2):55-60 [Abstract]Hehme N. GSK’s pandemic vaccine development: from 1st to to 2nd generation candidate vaccines. 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Released Mar 1999 [Full text]Iomai. Iomai awarded government contract, totaling $128 million, to develop dose-sparing patch for use in an influenza pandemic. Jan 17, 2007 [Press release]Keitel W. A phase I-II, randomized, controlled, dose-ranging study of the safety, reactogenicity, and immunogenicity of intramuscular inactivated influenza A/H5N1 vaccine given alone or with aluminum hydroxide to healthy adults. Presented at the Options for the Control of Influenza VI meeting, Toronto, Jun 2007Kotalik J. Preparing for an influenza pandemic: ethical issues. Bioethics 2005 Aug;19(4):422-31 [Abstract]Kreijtz JH, Bodewes R, van Amerongen G, et al. Primary influenza A virus infection induces cross-protective immunity against a lethal infection with a heterosubtypic virus strain in mice. Vaccine 2007 Jan 8;25(4):612-20 [Abstract]Kresse H. Author interview with Hedwig Kresse. Aug 2, 2007Lauerman J. Glaxo, Novartis, hurt by drug setbacks, may lose flu-shot race. Bloomberg News. 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Jun 5, 2007Working Group for Pandemic Influenza Preparedness. Letter to Congress. May 23, 2006Working Group for Pandemic Influenza Preparedness. Letter to Congress. Nov 10, 2005 [Full text]Zangwill K, Campbell J, Noah D, et al. Evaluation of a third dose of subvirion H5N1 influenza vaccine (rgA/Vietnam/1203/04 x PR8) in healthy adults. Presented at Options for the Control of Influenza VI, Toronto, Jun 17-23, 2007Back to toplast_img read more

Ground beef suspected in two-state E coli outbreak

first_imgJun 25, 2008 (CIDRAP News) – Federal and state officials yesterday reported an Escherichia coli O157:H7 outbreak that has sickened at least 24 patients in Michigan and Ohio, and state officials say their investigations are pointing to ground beef as the likely source.So far, 24 cases have been linked though epidemiologic studies and genetic fingerprinting to the outbreak, the US Centers for Disease Control and Prevention (CDC) said in a statement yesterday. Eleven of the patients are from Michigan, and 13 are Ohio residents.The CDC said illness onset dates for the patients were between late May and early June. Fourteen patients were hospitalized, and one patient developed hemolytic uremic syndrome (HUS), a potentially deadly kidney condition. No deaths were reported.While urging consumers to take precautions to avoid E coli exposure from ground beef and other possible sources, the agency did not specify a suspected source of the infections. However, Ohio officials today confirmed that E coli O157:H7 found in a raw ground beef sample provided by one case-patient matched the outbreak strain, according to a joint press release from the state’s agriculture and health departments.The contaminated beef was purchased at a Kroger Marketplace in Gahanna, Ohio, but officials said beef purchased from other sources may also be tainted and that consumers should observe ground beef precautions. A second sample bought by a consumer from a Kroger store in Fairfield County tested negative for the pathogen, but authorities did not say if the consumer was involved in the outbreak.Robert Boggs, director of the Ohio Department of Agriculture, said in the press release that the department was working with the US Department of Agriculture on a trace-back investigation.Ohio officials also said today that 17 state residents have been sickened in the outbreak so far, four more than the CDC’s total from yesterday, and that there were two more probable cases.In related developments, Michigan’s Department of Community Health (MDCH) yesterday issued a public health alert because more than half of its case-patients reported purchasing and consuming ground beef from Kroger stores. A product trace-back investigation is underway, and other retailers and outlets might be identified, the department said.MDCH officials also said they have confirmed 15 E coli cases that are linked to the outbreak, four more than the CDC’s total yesterday.Don Koivisto, director of the Michigan Department of Agriculture, said in the statement that Kroger is fully cooperating with state and federal investigators.E coli O157:H7 outbreaks are most often associated with ground beef, though some outbreaks in recent years have involved fresh produce. The strain produces a toxin that causes diarrhea—often bloody—and abdominal cramps but typically no fever. The illness usually resolves in 5 to 10 days, but it can cause HUS in 2% to 7% of patients.See also:Jun 24 CDC press releasehttp://www.cdc.gov/ecoli/june2008outbreak/index.htmlJun 25 press release from Ohio agriculture and health departmentsJun 24 MDCH public health advisoryhttp://www.michigan.gov/mdch/0,1607,7-132-8347-194926–,00.htmllast_img read more

WHO foresees problems with pandemic severity index

first_img May 11 WHO statement on pandemic severity assessment In the May 11 statement about severity, the WHO said the novel H1N1 influenza virus seems to be more contagious than seasonal flu, but typically causes “very mild illness” in otherwise healthy people. The statement also said that most people, with the possible exception of older groups, are likely to have little or no immunity to the virus. The WHO is gathering as much information as possible to help countries assess their vulnerability and fight the disease, she said. Instead of issuing a severity index, the WHO will base its guidance on a concept paper, issued on May 11, that outlines key severity issues and indicators that help countries assess their own vulnerability to the virus. She said severity is based on three components: the virulence and transmissibility of the virus, the vulnerability of the population, and the capacity of a country to fight the disease. All three components can vary across countries and pandemic waves, Briand said. “This is why it’s hard to have an index.” See also: May 13, 2009 (CIDRAP News) – A World Health Organization (WHO) official today signaled that the agency is stepping back from plans to develop a way to grade pandemic severity, because its experts believe severity will vary from place to place, making the development of a severity index difficult and its use impractical.center_img Briand repeated that the WHO pandemic alert phases refer to geographic spread and transmission patterns, but not severity. The WHO will continue to look at severity assessment. “In terms of linking, necessarily, phases with severity, let’s see if it’s useful, but it’s probably not so useful,” she said. Sylvie Briand, acting director of the WHO’s Global Influenza Programme, told reporters at a media briefing today that the agency’s technical experts have discussed a severity index several times, and they understand that pandemic severity is a key piece of information that governments use in response planning. But even within the same country, severity can vary among regions and during different waves of illness. “Having one indicator to describe all these varieties of situations was not very helpful,” Briand said. May 11 CIDRAP News story “WHO: H1N1 flu more contagious than seasonal virus”last_img read more