Vaccine-derived polio case in Nigeria puts eradication milestone in question

A confirmed case of vaccine-derived polio in Nigeria greatly complicates global plans to retire the trivalent vaccine next year and switch to the bivalent formulation. The polio eradication program is now between rock and hard place, with logistical momentum building for the switch but a possible public health emergency should the switch go ahead as planned.

In rare instances, the live oral vaccine can mutate, circulate and paralyze like its former self. Most cases of circulating vaccine-derived poliovirus (cVDPV) are caused by the type 2 virus in the trivalent vaccine, scheduled for retirement in April 2016. But the type 2 component of the vaccine both causes and protects against cVDPVs. In a Catch-22, the trivalent vaccine can’t be withdrawn until it stops the problem it is causing. Pulling the vaccine before halting type 2 cVDPVs would lead to a growing immunity gap and create the conditions for potentially large outbreaks.

Prior to the Nigerian case of cVDPV reported last week, Pakistan had caused the greatest concern with recent sewage samples testing positive for cVDPV. Nonetheless, the World Health Organization confirmed in April the scheduled replacement of trivalent vaccine with bivalent set for April 2016. The bivalent vaccine immunizes against only types 1 and 3 of the poliovirus. Type 2 appears to be long gone, last seen in India in 1999.

The logistics of the switch are daunting: 156 countries currently using or stockpiling the trivalent vaccine need to stop and switch to bivalent at the same time. Every dose of trivalent vaccine administered afterwards creates the risk of type 2 vaccine-derived virus.

In addition to the heavy logistical burden in the field, the switch also requires coordination among manufacturers who must scale back and eventually stop making the trivalent formulation and ramp up bivalent production. Once on, the switch is difficult to turn off.

"An absolute prerequisite"

Until recently, extinguishing all circulating vaccine-derived viruses was an unambiguous precondition for the switch. The eradication endgame plan states that “validation of the elimination of persistent cVDPV type 2…” must precede withdrawal of the trivalent vaccine. The US Centers for Disease Control (CDC) concurred that “persistent cVDPV2s need to be eliminated before the withdrawal of tOPV [trivalent vaccine].” Earlier this year, Paul Rutter, spokesperson for polio eradication's Independent Monitoring Board, said: "My understanding is that the switch could not happen unless cVDPVs are stopped—it is an absolute prerequisite."

No longer.

WHO’s Strategic Advisory Group of Experts (SAGE) decides vaccine policy. SAGE will meet again in October. “The SAGE is not only going to look at whether there is circulation,” said WHO spokesperson, Sona Bari, in early June. According to Bari, SAGE will also consider "what steps have been taken to stop circulation, what immunity levels are like, etc.” 

The Independent Monitoring Board (IMB) backed off from its earlier more absolute position after SAGE gave its go ahead for the switch. Said IMB spokesperson, Paul Rutter: “making a judgement about what constitutes a 'showstopper' would be to second-guess SAGE."

Earlier this year, a modelling study warned of a worrying possibility that vaccine derived virus would still be circulating next year when the switch is set to occur. A co-author of the study, Kimberly Thompson, expressed concern back in February that "It's possible that world leaders will decide to coordinate OPV2 cessation in April 2016 without being 95% confident that cVDPV2 transmission has stopped in Nigeria or Pakistan." At the time, Thompson believed “Pakistan may be more of a threat to global cessation than Nigeria." And subsequently, immunization efforts in Nigeria included measures to drive down cVDPV risk, particularly by vaccinating with the trivalent vaccine. As recently as June 22, Thompson believed Nigeria “can be OK in April 2016 at the time of the switch.”

After the Nigerian cVDPV case last week, however, Thompson stated that "if global health leaders want at least 95% confidence that cVDPV2 transmission has stopped in Nigeria prior to coordinated OPV2 cessation they will need to delay cessation beyond April 2016." Polio’s annual infection cycle is at its low ebb in the month of April. Consequently, a delay in the switch would likely push the date a full year to April 2017.

Pakistan too remains a risk for having cVPDV come next April, according to Thompson, although the risk in both Pakistan and Nigeria can be reduced by the number and quality of vaccination campaigns using the trivalent vaccine.

Thompson and co-authors at the CDC said in a recent paper that switching to bivalent vaccine while vaccine-derived virus circulated “would represent a public health emergency…” WHO already declared polio a Public Health Emergency of International Concern (PHEIC), back in May 2014. The CDC raised polio to a maximal, Level 1 crisis in 2011.

Regarding the schedule for the switch, the Gates Foundation deferred to SAGE. Said foundation spokesperson, Rachel Lonsdale, “The SAGE will review the plans for the switch this fall and make the decision if it is moving forward next year.”

A WHO spokesperson made no comment to an emailed request.

[Article updated at 11:33 am and 11:52 am 7/6/2015]

[Article updated at 3:33 am 7/7/2015]

Has Gavi moved the needle in vaccinating the world's children?

Gavi, long above the fray and untouched by vituperations over aid effectiveness, has come under scrutiny in a paper from the Center for Global Development (CGD). The paper found Gavi “failed to increase vaccination rates for diseases covered by cheap, existing vaccines” and did little better with new, more expensive vaccines. The study came with important caveats but, together with findings of other researchers, jeopardizes not just Gavi’s gold standard status but challenges its—indirect—claim to have saved millions of lives.

Gavi is the poster child of global health. As Bill Gates said recently: “Every time people look at aid money and say what’s the most impactful thing they can find in that whole space, Gavi gets ranked at the very top.” Gavi began as the Bill & Melinda Gates Childhood Immunization Program, and the “work that the foundation has done in vaccines through Gavi,” continued Gates, “has been the most important thing we’ve done.” As a result, “we’ve saved millions of lives,” seven million, according to Gavi, since it began in 2000.

The CGD’s Justin Sandefur agrees that “vaccines are saving millions of lives—I have no doubt about that.” But Sandefur and colleagues examined, “the causal effect of giving Gavi funding in terms of increasing number of lives saved…” He notes that even Gavi does not claim causality but to have helped developing countries save millions of lives. “If you read very carefully, it doesn’t make a clear, causal attribution to Gavi funding doing that,” said Sandefur.  But, “I don’t think that would be a lay person’s interpretation of what’s on the website necessarily.” Readers—and perhaps funders—infer causality. Bill Gates does.

But it is actually a hypothesis that, over the last 15 years and with a budget of $7 billion, Gavi increased the number of children vaccinated, thereby saving millions of lives. “Certainly we can’t corroborate the full headline numbers,” said Sandefur. For the classical vaccines, DPT (Diphtheria, Pertussis, Tetanus) and Hepatitis B vaccines, “we’re not finding any impact,” said Sandefur. CGD found immunization rates were a function of national income, not Gavi support. The CGD study compared countries near the eligibility threshold for Gavi, national income of $1,000 per person. If Gavi raised vaccination rates, there should be a jump right at the eligibility cut-off, because of the sudden jump in available funding.

But there is no jump for the older, inexpensive vaccines, DPT and Hepatitis B. Coverage for those Gavi-supported vaccines looked the same as for measles, which Gavi did not fund.

Gavi spokesperson, Rob Kelly, countered that “The paper misinterprets the statement that Gavi has immunized an additional 440 million children to mean that those children would not have been immunized at all in the absence of Gavi support.” Kelly acknowledged, that "many of these children would have been reached in the absence of Gavi support, but with fewer vaccines.”

Rolling out newer, more expensive vaccines has been a major emphasis for Gavi, both to reduce inequities (it used to take decades for new vaccines to reach the developing world) and to further reduce vaccine-preventable deaths from diarrhea, for example. According to Kelly, “The data makes it clear that the very large majority of Gavi supported vaccines were not in country programs prior to Gavi support.” 

However, CGD found only “small and statistically insignificant effects for the three high-priced vaccines promoted by Gavi,” Haemophilus influenza type B, pneumococcal disease, and rotavirus. According to Sandefur, this is because “…the rotavirus and pneumo vaccines simply haven’t had that wide an adoption in the lowest income countries—yet.” Sandefur said the absence of Gavi’s impact on vaccination for the older, cheaper vaccines is “probably the main thing people are going to take away from the paper,” rather than the “non-robust, positive results on the newer vaccines.”

Fungibility: how even free didn't work

The countries receiving Gavi support seem to spend the money elsewhere: “subsidized vaccines appear to have displaced domestic vaccination spending in countries near the threshold,” concluded the CGD study. The policy implications, said Sandefur, are that “delivering cheap, already existing vaccines to these middle-income countries with millions and millions of poor people is probably not going to accomplish much.” Such countries include India, China and Ghana, for example and “account for a huge share of the global poor.” They also account for a huge share of the lives Gavi claims to save.

The fungibility of aid and vaccine support in particular are not new issues. A Gavi-funded study raised the concern of whether Gavi’s Immunization Support Services (ISS) program displaced national government vaccine spending. Results of the 2007 final report were “inconclusive.” But it said ISS was “the easiest source of funding to meet [national immunization program] priorities…” Consequently, the report recommended more effort to ensure that ISS “does not become the funding source of first resort.” The analysis found worrying signs. Without ISS, spending on activities most likely to raise vaccination rates fell in 20 of 27 countries examined, by a median 4%. Although the changes were not statistically significant, it was “possible that ISS funding has displaced other sources of funding,” a result confirmed by the more recent CGD study.

"Near" the cutoff: The slippery slope to no impact

What about much poorer countries not near the threshold? Sandefur said he is “agnostic” about the impact of Gavi on much lower income states like Niger and Burkina Faso. “Our results are focused on countries near the threshold.” However, for the CGD analysis, “near the threshold” actually means income levels down to $500 a year per person. Thus the CGD findings of no impact technically extend to Gavi-supported, low-income countries like Chad, Somalia and North Korea.

What about still poorer countries? Sandefur cautioned that, “Philosophically, there's also an argument to be made that the causal effect we estimate here applies strictly to a hypothetical country right on the threshold, just teetering on the edge.” This would limit the comparison to Gavi-supported Ukraine, on one side of the cut-off, and the Philippines on the other. However, there's no strict rule about how far to extrapolate these causal effects. “The more you extrapolate, the more damning our conclusions,” said Sandefur. “I would go beyond Ukraine, but stop short of the whole world.” Sandefur noted, however, that methodological objections are not raised to desired results, only negative ones: “if we had found great, positive effects, everybody would be eager to extrapolate to all countries.”

Sandefur acknowledged there is a basis for extrapolating the findings of no impact from Gavi even down to very poor countries. “If there was a big switch in the impact, you would expect to see some big jump in the vaccination rates between lower income and middle income and what I’m saying is you don’t really see that. There’s not some sudden regime shift when you move from low income to middle income countries.” In addition, vaccination rates before and after Gavi started in 2000 can be compared to “see if you see any jumps at that point,” after Gavi kicks in. “And you don’t,” said Sandefur.

A major methodological problem for measuring Gavi’s effect in poor countries is that there is no control group. According to Sandefur: “All very poor countries either got Gavi aid, or were eligible to get Gavi aid and didn’t for some reason that probably implies they're a bad control group…” Absence of a control group has led to “fairly wild extrapolations from what's happening in non-poor, non-Gavi countries,” explained Sandefur.

A 2008 paper from the Institute for Health Metrics and Evaluation (IHME) estimated 7.4 million additional children were vaccinated since Gavi came into being. But Sandefur questioned “whether there are really strong grounds for causal inference or attribution to Gavi on the basis of those regressions, to be blunt.” And indeed, the IHME paper does not assert causality, instead reporting that “we have not addressed whether the increases in DTP3 coverage that have occurred in GAVI ISS recipient countries would have occurred in the absence of GAVI’s support.” 

Gavi support did lead to an increase in reported vaccination coverage. Countries received rewards for increasing vaccination rates and reported rates duly rose, as high as 80–100% in countries like Niger and Mali where surveys put coverage much lower, closer to 40–60%. Whether a positive impact of Gavi would remain absent over-reporting was “an unanswered question,” according to IHME. 

CGD confirmed IHME’s 2008 results. “There is clearly evidence that there was manipulation of the DPT data by Gavi-eligible, ISS-eligible countries,” said Sandefur: “So progress there seemed to have been exaggerated.” Yet, even with the benefit of immunization over-reporting, CGD still found no impact from Gavi.

An undesirable conclusion

Gavi was started because it seemed to many that the urgency had gone out of vaccination efforts led by the World Health Organization and UNICEF. But IHME’s 2008 study found that perception was mistaken: “Globally, survey-based coverage shows that the yearly increase is fairly constant before and after the establishment of Gavi…” Few would question whether Gavi was a good idea. But the intrepid Gates-funded researchers at IHME wondered: “Would Gavi have been implemented if there was less of a perception that improvements in DTP3 immunization coverage during the 1990s were stagnating?” Melinda Gates continues to believe in the now-disproven stagnation hypothesis. Speaking last month of the Gates Foundation’s entry into vaccination, she said: “We started to study it. We started to learn how we had this incredible vaccine system that had kind of crumbled over time.” 

Melinda explained that “we” meant more than just the Gates Foundation. “When I say ‘we,’ I don’t want people to think we’re taking credit for all this,” pointing to the importance of partners. However, the Gates Foundation annual letter laid indirect claim to reducing child mortality: “The last time we cut the child death rate in half, it took 25 years. We will do it again in 15 years.” It’s a story everyone wants to believe. Gavi is a “game-changer,” gushed Melinda Gates’ interviewer. Yet quite possibly, even the very poorest countries needed no help and “we,” however defined, contributed nothing to saving the lives of children, only the perception of saving millions of lives.

Gavi subsumed the Expanded Program on Immunization (EPI), officially begun in 1974 and run by UNICEF and WHO. EPI hoisted vaccination rates from as low as 5% all the way to a reported 80%, a goal declared as achieved in 1990. Today, with Gavi in charge, WHO recently said immunization “stalled in recent years”—the needle stuck at the familiar 80% level.

Gavi recently completed a new $7.5 billion round of financing and promises to save six million more lives.

Have we already seen the best malaria vaccine prospects?

For half a century, scientists century have known one weird trick for eliciting immunity to malaria:  allow a person to be bitten 1,000 times by mosquitoes that have been irradiated. It works. In 1967, researchers reported sterilizing protection in mice from this approach. One thousand bites worked in later human experiments too, eliciting protection in 90% of the small group tested. Decades of malaria research has focused on bottling up the irradiation magic into a vaccine. But the most promising leads have been tried without success, raising the question: is the best yet to come? Or are we scraping the bottom of the barrel?

Malaria infection starts with the bite of a malaria-carrying mosquito which injects malaria spores (“sporozoites”) into humans. Radiation-damaged sporozoites, however, prompt a highly protective immune response while being too weak to survive and develop into disease.

A sporozoite consists of more than one thousand response-provoking, antibody generators or “antigens.” In the 1980s, scientists examined the successful antibody responses to the irradiated sporozoites. The winner, going away, was CSP or circumsporozoite protein. Other antigens were discovered too, with acronyms like TRAP and LSA-1. But none dominated the immune response like CSP, making it the clear favorite for a vaccine that only presented the parts of the parasite needed to elicit immunity, a “subunit” vaccine.

The CSP gene was sequenced, also way back in the 1980s, and optimism ran high that a vaccine was within reach. Much lengthy and laborious research eventually produced a candidate vaccine based on CSP called RTS,S. It was “the logical extension of more than a decade of research built on the hypothesis that a subunit vaccine based on the CS protein would protect humans from malaria infection,” as the vaccine’s co-inventor, W.R. Ballou, put it.

In 1997, RTS,S protected a remarkable 6 out of 7 people. However, fast forward years and hundreds of millions of dollars to 2014, and field trials now show the once-promising RTS,S protects only a disappointing 28% of children vaccinated. Although based on CSP, the champion of antigens, RTS,S delivered less than a third of the 90% benefit promised by the whole organism approach.

Many different approaches, combinations, formulations and technologies have been tried but none have produced a vaccine as good as even the mediocre RTS,S. Malaria researchers have helped pioneer a number of different technologies like the use of viruses and DNA as delivery vehicles. Adjuvants, used to amplify immune responses, have also been varied and are still being tested to see if they can improve the protective benefit of different vaccine candidates.

However, in recent years, little new ground has been broken. “A lot of people have been focused on various formulations with the currently available candidates,” said Lee Hall, Chief of the Parasitology & International Programs Branch at the National Institutes of Health. “There was some ramp up as people looked at a number of different ones. But if they didn’t pan out in the early studies then they weren’t moved forward.”

Among alternative to CSP, only one antigen, based on TRAP, is now in Phase IIb clinical trials. The vaccine protected only 13% of vaccinees in an earlier study. There is one other single-antigen candidate, FMP012, that has pending results from a Phase I trial. Mainly, however, vaccines aimed at protecting against malaria infection are overwhelmingly variations on CSP, both in the PATH Malaria Vaccine Initiative pipeline and the World Health Organization “Rainbow” table. Some projects combine RTS,S with other vaccines, in search of additive or synergistic effect. Also, scientists recently succeed in making a full-length CSP for study. (RTS,S only uses a portion of CSP.)

Many combinations are possible and the number of antigens could be increased, although technical and regulatory issues begin to arise. “Obviously people want to go for something is likely to be successful,” said Lee Hall. “They don’t want to embark on something that is so complex at the outset that the chances of it making it through the development process is low.” How many antigens a subunit vaccine could deliver is not known. According to Hall: “If it turns out that it’s two or five, that might [be] possible to do. If it turns out you need 50, then it turns out to be a lot more difficult.”

Some scientists see the failure of RTS,S as the undoing of the subunit approach. The success of the irradiated sporozoites served “as justification for the ensuing decades of research aimed at identifying the ‘right’ vaccine antigen,” or antigens wrote Mahamadou Thera and Christopher Plowe. “[I]t is reasonable to believe that it may be possible to construct a multistage, multi-antigen recombinant protein that improves on the efficacy of RTS,S,” they continue. But Plowe is skeptical that high levels of protection are possible. In a book chapter version of the article, Plowe added: “it seems not unlikely that vaccines that target 2, 5, or even 15 of the 5,000 gene products will still fall short of the high levels of protection seen with radiation-attenuated whole-organism vaccines when delivered through the bites of infected mosquitoes.”

According to Timothy Wells, Chief Scientific Officer at the Medicines for Malaria Venture, RTSS “even as a partial vaccine, is a massive triumph immunologically.” The human immune response to malaria is transient and requiring, on some estimates, 10 malaria infections, according to Wells. “This is why making a vaccine is close to impossible,” said Wells. Perhaps informed by this conclusion, the PATH Malaria Vaccine Initiative (MVI), funded by the Gates Foundation, has been quietly dropping candidate after candidate. Two projects testing multiple antigens have been dropped, one as long ago as December. However, that cancelation was only recently reflected in MVI’s portfolio which “was just updated last week,” the week of May 10, according to PATH spokesperson, Kelsey Mertes. One other canceled vaccine project “is still included on the portfolio because it hasn’t been closed out yet,” according to Mertes. Cancelled projects remain in the portfolio “until the contract is closed out and the last payment made,” Mertes explained. The portfolio still contains two studies of RTS,S given with another vaccine. Results are in for one but, perhaps suggesting the outcomes were not spectacular, Mertes did not reply to an email asking if it would move forward into the next phase of trials. The MVI portfolio looks increasingly barren as the sole remaining active trial for a protective pre-erythrocytic vaccine will report results later this year.

The search continues technically, although at the very earliest stage of the pipeline with any actual vaccine many years away. According to Mertes, MVI “is undertaking target validation work” on over 25 candidate antigens for a protective, pre-erythrocytic vaccine. However, science suggests that future discovery of a highly protective antigen or antigens is unlikely. Malaria has some 5,000 genes, but there are not 5,000 potential vaccine targets. Malaria genes produce just under 2,000 proteins. Vaccine targets are fewer still because not all the proteins are seen by the human immune system. Indeed, according to Stefan Kappe: “The number of surface and secreted proteins we identified is much lower, less than 100.” Kappe leads a group at Seattle Biomed that began assessing new antigen candidates in late 2012 for MVI. The project is expected to take six years or more. “Most of the novel targets are not published yet,” said Kappe.

It is not the first such effort but, because of its comprehensiveness, it could be the last.

In 2011, a group at New York University published results of efforts, supported by the Gates Foundation and others, to find new candidate antigens for a malaria vaccine. The researchers tested 34 new antigens, but concluded: “In summary, we failed in our attempt to discover powerful protective non-CS antigens…” Researchers saw no reason to look any further for other antigens. The study’s lead author, Satish Mishra, wrote in email: “We can’t rule out the possibilities in science but we as far as we understand it’s very unlikely” that there are important, yet to-be-discovered antigens. More bluntly, according to Mishra: “We have already checked the best candidates and already given up the new candidate search.”

Claim of Possible Drug-Resistant Malaria in Angola Withdrawn

A paper reporting a possible case of drug-resistant malaria in Angola appeared last July (reported here), meeting with scathing incredulity and direct calls for retraction from the World Health Organization and some members of the malaria research community.

The surprising firefight appears to have been concluded, not with retraction but the publication of letters from the authors of the original paper and its detractors at WHO and Mahidol University. The paper’s authors now acknowledge that “our report of a Vietnamese worker returning from Angola with severe Plasmodium falciparum malaria not responsive to artemisinins is unlikely to indicate that artemisinin resistance has reached Angola.”

The paper and letters appeared in Emerging Infectious Diseases, published by the Centers for Disease Control (CDC).

Critics point out that the delayed clearance time seen in the case was nearly ten times slower than that seen in drug-resistant malaria in Southeast Asia, the only region in the world with clinically-verified resistance to artemisinin-based anti-malarials. Genetic testing after the publication of the paper did not find any of the mutations in the K13 gene associated with resistance. Also, the drug used in the case came from a batch that was withdrawn because of quality issues.

In rebuttal, the authors of the original paper note that the drug used, while substandard was far from lacking any activity. The paper is not being withdrawn and the case is not closed, say the authors: “the reasons for the lack of response to artemisinins in this patient remain unknown and are under continued investigation.”

WHO also says it is still looking into the same geographic area of Angola from which the disputed case originated.

Olivo Miotto, who previously predicted the paper would be retracted, said more recently “it was a mess-up, as was suspected at the time by those more interested in science than fiction.”

According to Annette Erhart, one of the paper’s authors, the Vietnamese investigators knew that publishing the case would expose them “to criticisms about the way the patient was managed.” The group published nonetheless because “for the first time, they were confronted to a situation where AS [artesunate] did not work at the dosage recommended by the national guidelines.” Continued Erhart: “The attitude of the WHO is discouraging anybody to report suspected resistance cases, while it should be actually the opposite.”

WHO’s Pascal Ringwald, contacted last September about the case, said “Globally it is amazing how journalists misunderstand artemisinin resistance and they do not investigate on what should be investigated.” Although the paper had been published by the CDC and elicited public statements of concern from prominent malaria researchers, Ringwald insisted on his own knowledge: “I do not know which is or are your sources but I think that you do not trust me.” The case, he said, "is absolutely not interesting and not important.” Ringwald forbade all further inquiries: “In the future please use your other sources of info and do not contact me for any kind of reason.”

A ceasefire of sorts appears to have been brokered. Said Miotto: “I think everyone is just letting it drop—not worth any arguments.” Patrick Kachur, chief of malaria at the CDC, declined to answer questions about the matter directly, referring inquiries to the CDC press office. Kachur did allow that “I was hoping these [letters] would be ready to share a lot sooner.” 

Malaria vaccine disappoints, shifts strategy for eradication

Five years ago, many in the malaria field believed eradication would be “impossible” without an effective vaccine. However, Bill Gates’ 2015 annual letter proposed dispatching malaria “within a generation,” not through vaccination but mass screening and drug administration. In it, Gates relegated vaccines from the front lines to a mop up role, less protecting people from malaria than preventing further transmission in the event of infection, “so that once an area is cleared of the parasite, it stays clear.” 

Vaccines are much fallen.

Read the rest at Humanosphere

Bednets failing to reduce malaria in Uganda, maybe everywhere

Since 2000, billions of dollars have been spent on a massive and multipronged anti-malaria effort supported by the World Health Organization, groups like Nothing But Nets, the Global Fund to Fight AIDS, TB and Malaria and other organizations. As a result, WHO says, malaria mortality has fallen by about 50 percent globally in the past 15 years.

But how certain are we of this success story, and what’s really driving it? Is it the hundreds of millions of bednets?

“That’s the million dollar question,”  said Moses Kamya, speaking recently at the University of Washington’s Institute for Health Metrics and Evaluation (IHME) in Seattle.

Kamya is a professor of medicine at Makerere University in Uganda. He presented an unpublished study showing persistently high transmission and increasing incidence of malaria in rural Uganda despite universal bednet coverage and effective anti-malaria treatment.

Kamya findings suggest that some experts are quietly, sometimes reluctantly, beginning to dig deeper into the assumption that bednets are as effective as claimed.

Read the rest at Humanosphere...

Nigeria: Progress and All that is Wrong with Polio Eradication

During high season for polio this year, Nigeria has seen only one case of paralysis caused by the wild virus – an achievement which, if viewed in isolation, can be hailed as a great global health success.

But the single-minded focus on polio eradication appears to have left routine immunization behind. Measles deaths spiked last year not only in Nigeria but globally.

Now, ironically, Nigeria’s exceptionally poor immunization system is obstructing the goal of polio eradication.

Read the rest on Humanosphere...

Gates Foundation Crushing Polio in Nigeria

It's high season for polio in Nigeria--and there have been no cases for seven weeks. The Gates Foundation arguably runs the polio eradication effort, and apparently to good effect.

The remarkably low numbers seen in Nigeria are probably not due to missed cases. The quality of surveillance can be measured in a number of ways. There usually is at least one case of non-polio paralysis a year for every 100,000 children. Below that ratio, surveillance is considered inadequate. To distinguish polio from non-polio paralysis, stool samples must be analyzed, with a goal of testing 80% of cases. Nigeria's scores on both these measure have been climbing since 2006. The stool sample rate now approaches 100%.

It is difficult to descry changes in these measures easily attributable to new and improved management. Regardless, in a kind of pincer movement, better surveillance and increasing quality of immunization campaigns are slowly crushing polio.

Nigeria might or might not make it to the end of 2014 with no cases. If it does, transmission in the country could be declared as halted, which might be important for meeting the global eradication deadline of 2018. However, Pakistan, which faces an intense although geographically circumscribed polio explosion, unquestionably will not halt transmission this year. If the eradication timeline is taken literally, Pakistan's situation will require adding one year to the schedule, i.e. missing yet another eradication deadline and likely adding roughly $1 billion to the budget. 

The Independent Monitoring Board, de facto interpreter of the eradication plan and arbiter of progress, will have a report out soon.

Polio: What the “other” global health crisis tells us about Ebola

The World Health Organization (WHO), technically responsible for the world’s health and declaring emergencies, is actually in charge of neither. In late July, before declaring Ebola to be a global public health crisis, WHO’s Emergency Committee declared polio a public health emergency of international concern. Ebola only graduated to the same status a week later after American health care workers became infected. The world then ignored WHO’s alarm for weeks as Ebola exploded. The other “emergency”—polio—overshadowed an actual Ebola crisis, and makes visible WHO’s decline to infantilized order taker and the primacy of the Gates Foundation.

Polio "Emergency"

When WHO declared polio to be a public health emergency on May 5th, 2013, the risk of polio spreading sat near its lowest level in human history.

Polio is more than 99% extinguished compared to 1988 when there were 350,000 cases in 125 countries. The polio “emergency” came not from risk to public health but risk of not making the eradication schedule. To make a 2018 deadline, polio transmission must be stopped by the end of this year. Similarly, in 2011, the CDC declared polio to be a maximal, Level 1 crisis to meet a now-passed 2012 deadline. Still today, the CDC Emergency Operations Center recognizes two emergencies: polio and Ebola.

Calls for WHO to make polio a global health emergency originated from the Independent Monitoring Board (IMB) of the polio eradication initiative. Set up in 2010, IMB says it was “convened at the request of the World Health Assembly.”  However, there is no World Health Assembly resolution that mentions or requests an independent monitoring board. “I have just had a good look too,” said IMB spokesperson, Paul Rutter, “and can't find it either.”

Notwithstanding the unclear provenance of IMB’s authority, the WHO Director-General in effect reports to IMB. According to IMB’s charter, the Director-General must “immediately inform the relevant Ministry of Health and donor or partner agency” of IMB recommendations and establish corrective action plans “within 4 weeks of notification.”

In late 2013, the IMB expressed its desire that WHO declare polio to be a public health emergency. However, the International Health Regulations governing emergencies emphasize “public health risk,” not schedule risk. But the campaign for a polio emergency continued. At the end of January, the United States’ representative to the WHO Executive Board, Nils Daulaire, asked WHO to declare polio to be a public health emergency and set a deadline of mid-May, 2014.

Before being named US representative to WHO, Daulaire served for more than a decade as president and CEO of the Global Health Council. Among its function, the council selected the winner of the $1 million Gates Award for Global Health. Under Daulaire, from 2000 forward, the Global Health Council received $36 million from the Gates Foundation. In 2006, Daulaire’s wife went to work at the foundation, continuing there until the end of 2013.

Daulaire has said he "does not see the Gates Foundation or private entities as having a rightful role in establishing WHO’s priorities.” He dismissed suggestions that the foundation has an outsized role although he said: “There are member states who believe the Gates Foundation has more influence than it ought.” Daulaire said it is “entirely wrong” that the United States is increasing the foundation’s role.

Polio eradication has topped the Gates Foundation’s priorities for several years. In 2011, then foundation president, Tadataka Yamada, answered critics of the polio-centric agenda saying: “They are right. We are overemphasizing polio eradication.” Earlier this year, Bill Gates said “polio is the single thing I work on the most.”

The WHO Executive Board did not vote on Daulaire’s proposal for a polio emergency. The board, which rotates, did happen to include a number of countries impacted by polio: Pakistan, Nigeria, India and Syria. None of their representatives supported or mentioned the US call for a public health emergency. The United States itself has been polio-free for more than three decades. The CDC saw no increased threat to Americans. 

On May 5, just ahead of Daulaire’s deadline, WHO declared polio a public health emergency. On the same date, WHO reported a cumulative 239 cases of Ebola and 160 deaths in three countries.

Daulaire, according to Executive Board meeting minutes, also said “His Government attached high priority to strengthening the International Health Regulations and had established global health security as a key issue,” precisely where WHO would soon fail. However, according to a Reuters report, a 2011 proposal for a $100 million epidemics task force was shot down by member states. Also, budget cuts forced WHO’s Africa regional office to cut its epidemic team from 12 to four staff over the past two years. As Peter Piot, discoverer of Ebola noted, WHO budgets cuts were “approved by the USA and other member states.”

The polio emergency, sought and won by Daulaire, had been based on the worry that “Pakistan, Cameroon, and the Syrian Arab Republic pose the greatest risk of further wild poliovirus exportations in 2014,” according to WHO. Subsequently, neither Cameroon nor Syria exported polio and domestically experienced no onset of polio-induced paralysis since before the first declaration. Pakistan, where polio transmission has never been interrupted, continued to export polio—as it always has, although without having prompted a global emergency. Nonetheless, WHO concluded on July 31st that “the international spread of polio in 2014 continues to constitute an extraordinary event and a public health risk to other States.”

At the same time, WHO also reported a total of 1,323 Ebola cases, 729 deaths and even the export of the disease to a fourth country, Nigeria. However, Ebola apparently did not come up at the polio meeting, according to Vice Chair Robert Steffen: “with the targeted agendas I would not imagine that the polio [Emergency Committee] suggested there should be an Ebola [Emergency Committee].”

Unmentioned at the emergency meeting, Ebola had become uncontrolled more than a month earlier. On June 23rd. Médecins Sans Frontières (MSF) issued a press release declaring “We have reached our limits.” An MSF spokesperson said, “we are no longer able to send teams to the new outbreak sites,” which numbered more than 60 across Guinea, Sierra Leone, and Liberia. MSF, which described itself as the sole responder to the epidemic, said: “The epidemic is out of control.” The next day, WHO Ebola expert Pierre Formenty briefed top WHO officials in Geneva. Days later, the WHO Ebola situation report recognized “Currently, the coverage of effective outbreak containment measures is not comprehensive,” as Formenty’s presentation had shown. WHO updates began reporting cases and deaths not in sentences but using a grid. The rout was on.

The science of epidemiology should have been able to predict, albeit tentatively, when the efforts of MSF were doomed to fail. But just as with polio, epidemiology played no role in the timing of emergency declarations and international response. WHO’s emergency announcement came only on August 8th when there were 1,778 cases—including, for the first time, two Americans.

After the Ebola Emergency: No Response 

Declaring polio an emergency did not unleash vast new efforts to stamp out the disease. Most everything had already been done in the $1 billion a year effort —except consecrating eradication as the single most important public health issue in the world. The day after the polio declaration, the Gates Foundation blog explained that “The sounding of an emergency often is seen as a sign of distress, and news of this announcement certainly communicated that.” Indeed, the supposed emergency fueled headlines like “Polio, Spreading Abroad, Threatens US.” Not only was there no increased threat, the risk of spread was near historic lows. Instead “what this alarm really signals,” continued the foundation blog, was doing “what it takes to end this disease as quickly as possible,” that is, meeting the 2018 deadline.

When WHO declared an Ebola emergency, its declaration also did not unleash vast new efforts to stamp out the disease. WHO lacked resources to do anything itself while whatever heft the UN has was not applied. UN Secretary General Ban Ki Moon was not at Margaret Chan’s side as the WHO Director-General announced the Ebola emergency. Moon appears more frequently with Bill Gates. Gates partnered with Moon and the UN, not WHO, for the Gates Foundation vaccine summit that raised more than $4 billion for polio. And, as symbolized by an article co-written by the two on vaccination, Gates and Moon author the global health agenda, not WHO.

The world reacted to WHO’s Ebola emergency as if declared by a clerk. The CDC dispatched a small team to Liberia to areas that had not yet reported any cases. Its purpose was not to assist in containment but to assess preparedness which was found to be woeful. The CDC’s “surge” response dispatched 50 more disease control experts to be deployed within a month. Although issuing a travel warning to US citizens, the CDC was “not screening passengers traveling from the affected countries.” For the ongoing polio emergency, the CDC reported “an average of 60-70 people” working on eradication at its Emergency Operations Center.

Gates Foundation Plays Down Ebola 

For the Ebola crisis, the Gates Foundation pledged $1 (one) million to “help address the immediate need on the ground,” according to foundation CEO, Sue Desmond-Hellmann. But the next day, on its “Impatient Optimists” blog, the foundation optimistically moved on. A piece entitled “How to Prevent the Next Health Crisis,” explained how the next threat, cerebro-spinal meningitis, “could end up being far more destructive than the current Ebola epidemic.”

Three weeks later, on August 25, Desmond-Hellman tweeted about how “Nigeria is using what they’ve learned battling polio to contain the ebola outbreak.” The story was not about Nigeria as harbinger of inexorable spread but how polio eradication investments had saved the day. And indeed, the $1.5 billion being spent in Nigeria for polio might have contributed to extinguishing Ebola there.

Bill Gates weighed in on Ebola for the first time on September 10, more than two months after MSF said the outbreak had become uncontrolled. Gates tweeted about the foundation’s upcoming chat on Twitter:

The foundation now pledged $50 million; earlier in the year, it committed $1.8 billion to polio. The United States, now finally acting on Ebola, drew applause from Desmond-Hellmann: “The time to act on Ebola is now,” she said with the case count at 4,963. But just days and 2,507 cases later, Desmond-Hellman wrote of Ebola: “If the world doesn't learn from this outbreak, one day we’ll have a real pandemic on our hands.”

It was not the foundation’s job to detect and declare emergency outbreaks. But the foundation and Gates evaluated the Ebola threat and publically projected the conclusion that Ebola was no emergency.

Gates Foundation Running Polio Eradication

Gates is influential. “If … I need to go to the Indian parliament and say, ‘Let’s get serious about vaccines,’ ” said Gates, “then yes – since I’m giving my own money [on a] large scale and spending my life on it and I’m a technocrat – yes, that can be quite valuable.” In 2011, Gates had gone to the World Health Assembly and said it needed to get serious about vaccines. He explained to the assembly “how you can provide the leadership to make this the Decade of Vaccines.” The WHA followed Gates’ leadership advice and approved his initiative. Memorably, Gates also told the WHA:  "Our priorities are your priorities."

Not only did polio come to uniquely occupy the pinnacle position in international public health, the Gates Foundation has come to effectively run the eradication effort. The Director-General began answering to the Independent Monitoring Board in 2010. In 2011, a Polio Partners Group (PPG) replaced a meeting previously convened by WHO. WHO participates in the new group but is barred from serving as its chair by PPG bylaws. The PPG “was not summoned into existence per se” by act of the World Health Assembly, according to its current chair, John Lange. As with the IMB, there is no resolution requesting that the PPG be instantiated. Lange, now at the UN Foundation, previously worked at the Gates Foundation from March 2009 to June 2013. He was a foundation employee when elected PPG chair. Lange said the PPG was conceived at a meeting held not in Geneva at WHO but the CDC in Atlanta in December 2011, at or near the time when the CDC elevated polio to a maximum level threat.

Space for initiative-taking by WHO has been systemically closed off, as if child-proofing a room by blocking electrical power outlets. In 2013, a new entity, the Polio Oversight Board (POB), took over operational decision-making from WHO. According to Lange, the POB "effectively oversees and manages" the polio eradication effort, although “technically” the POB does not have authority over budgets, for example. Nonetheless, said Lange: "Its decisions are implemented." The first POB chairperson was Lange’s former boss, Chris Elias, president of global development at the Gates Foundation.

Gates Foundation, Not WHO, Sets Global Health Agenda

The Gates Foundation’s subjugation of WHO is not new. WHO lost its global leadership and capacity to set the world’s health agenda years before. At the 2007 Malaria Forum, for example, the convening power of the Gates Foundation, not WHO, brought together the world’s leading malaria researchers and policy makers. WHO Director-General Margaret Chan sat in the audience as Melinda Gates shocked her invitees by proposing to eradicate malaria. Malaria eradication had been tried and failed disastrously. However, Chan converted on the spot, jumped up and, taking the microphone, enthusiastically supported eradication. At the time of the Malaria Forum, the foundation had cumulatively invested $1 billion in malaria, starting with an early, $50 million grant in 1999. By contrast, the purchasing power of WHO’s budget in 2007 had fallen by almost 25 percent compared with 2000.

The foundation did not ask WHO, its Director-General or the researchers it invited to the conference for their opinion about malaria eradication. For polio, the World Health Assembly voted on and approved a resolution on eradication. But a Gates Foundation spokesperson, asked whether there would be a vote on malaria eradication, said: “Not as far as I know.” Arata Kochi, then the head of malaria at WHO, fought back against what he described as a foundation “cartel.” He was replaced after his memo leaked to the New York Times. In 2014, the president of the American Society of Tropical Medicine and Hygiene (ASTMH) is Alan Magill, the head of malaria at the Gates Foundation. The keynote speaker for this year's ASTMH conference is Bill Gates.

The Gates Foundation isn’t on the sidelines haphazardly supporting good causes but actively architecting global health policy. The “overemphasis” on polio comes from foundation plans for malaria eradication. As Bill Gates recently explained: “Polio we hope to get done by 2018. Then the credibility, the energy from that we will allow us to take the new tools we’ll have then and go after a malaria plan.” The current malaria plan was paid for by the Gates Foundation. A year after shifting malaria policy to eradication, in 2008, the foundation became and has remained the largest funder of polio eradication.

Absent this link to malaria eradication, the foundation’s overemphasis of polio makes little sense. Even Gates acknowledges that, among eradication efforts, polio is borderline. Smallpox he said, “was a good choice. Polio is a hard but reasonable choice." Much better is malaria, which he characterized as "a very reasonable choice.” At no time in the past or present has polio merited the world’s sole focus—unless for symbolic reasons. Other diseases, like diarrhea, are more prevalent and deadly. Polio, for all its awfulness, rarely causes death. 

The Gates Foundation has also hived off childhood immunization from WHO. The cleaving began in in 1998 with the introduction of the Bill & Melinda Gates Children’s Vaccine Initiative. The creators of this early initiative worried that WHO “might consider that we are trying to pre-empt their responsibility,” and worked to “find a way to present ourselves that avoids all presumption of a challenge to WHO." (Quoted in Muraskin, Crusade to Immunize the World's Children.)  The program eventually became what is known today as GAVI. The money for immunization goes to GAVI and no longer directly to WHO and UNICEF.  By 2008, any challenge to WHO was over. A GAVI governance change submerged WHO on a board with 28 other members, its vote counting as much as a representative from the vaccine industry.

WHO is no longer even in charge of global health statistics. The 2013 Global Burden of Disease was assembled and published by the Institute for Health Metrics and Evaluation (IHME). IHME was created by a $105 million grant from the Gates Foundation. Located at the University of Washington, IHME threw down the gauntlet years before, publishing papers on maternal and child mortality that publically contradicted figures from WHO on the front page of the New York Times. At a related 2010 conference, IHME chief Chris Murray said bodies like WHO were “not the definitive producers” of global health metrics. He proposed that WHO become a “disengaged guide,” like Consumer Reports or that WHO present comprehensive results without judging them, a model which Murray likened to A third, unmentioned alternative is for IHME to simply replace WHO as definitive producer of the world’s global health statistics.

Bill Gates as Global Health Visionary

Seizing control from WHO could be explained, perhaps applauded, given serious questions about its competence and serial, unsuccessful reform efforts. Gates, who made his career trouncing another anachronistic three-letter acronym, IBM, seems not to have considered trying to shore up international global health governance. Not global health but population control had been Gates’ initial focus in the 1990s. As he explained earlier this year "It was only when we found out about this phenomenal connection between improved health and reduced population growth that we felt: Great, let’s just make the foundation as big as possible to go after these health problems.” He courted and, in 2006, won the fortune of Warren Buffett for his foundation’s endowment, explaining at the time: "If you want to deal with billions of people, you need scale."

Institutions of civil society were inadequate. “We must be willing to look at the failure of collective action and see how we can change it,” Bill and Melinda Gates wrote in 2007. More recently, regarding democratic processes, Gates said: “The closer you get to it and see how the sausage is made, the more you go, oh my God!” He questioned whether in the United States, “can complex, technocratically deep things…can that get done?” It was unclear that democracy was equal to complicated modern problems. According to Gates: “The idea that all these people are going to vote and have an opinion about subjects that are increasingly complex – where what seems, you might think … the easy answer [is] not the real answer. It’s a very interesting problem. Do democracies faced with these current problems do these things well?”

How well has Gates done in the face of important global health problems? Prior to Ebola, AIDS represented the greatest global health crisis of the present era. Although AIDS is far from solved, the epidemic has been controlled by the free provision of anti-retroviral therapy (ART). Free ARTs saved lives and reduced transmission of the disease. The PEPFAR program, unexpectedly initiated and signed into law by George W. Bush, made ARTs free in the world’s hardest hit regions. Even Bono credited Bush and American taxpayers: “…10 million people owe their lives to the U.S…George Bush started it,” the U2 frontman said last year.

Bill Gates opposed free AIDS drugs, because of the “harsh mathematics of the epidemic,” as he wrote in The Independent. “[F]or each person who starts getting treatment today, 10 more people will need treatment tomorrow.” Gates cited cost estimates as high as $40 billion a year by 2020. Instead, prices were forced down, anti-retrovirals saved lives and turned the tide of the epidemic.

Aversion to Short-term Crises and Outbreaks

“The battleground is disease prevention, not treatment,” according to an early advisor to the foundation, Bill Foege. His philosophy might have informed Gates’ opposition to free AIDS treatment. Gates named a $60 million building on the University of Washington campus after Foege, saying: “On so many issues, from the importance of disease prevention to the details of how to get partnerships right… Bill [Foege] has pointed the way,” Foege replied:  “I’m grateful for the vision that not only worries about how to get vaccine into a child but is not diverted by the tyranny of the acute from changing the future.”

The Gates Foundation, shaped by Foege, is constitutionally averse to short term crises. When the foundation at last pledged a modest $50 million for Ebola, it made much of how it was its largest ever grant for a humanitarian emergency. The foundation might have viewed Ebola as an acute need potentially competing for resources needed for vaccination efforts or perhaps to rid the world of polio and malaria forever. 

The foundation presumably made assessments of the Ebola threat, but it is not clear how and by whom. The foundation does not appear to have a section or person dedicated to outbreaks. The portfolio of the foundation's Lance Gordon, neglected tropical diseases, perhaps comes closest to Ebola. Gordon did not reply to an email asking how the foundation assessed the Ebola outbreak.

The foundation prioritized meningitis vaccination above Ebola. Gates, perhaps uniquely, audaciously defended the slow response to Ebola, saying “I think it is amazing how the United States has responded to this.” He warned “it’s easy to forget just how much has been done” in response to what he called a “short-term crisis,” although he would not forecast when it would end. The unprecedented deployment of the military he attributed not to the exponentially expanding scale of the disaster but “the president who said let’s get the Department of Defense involved because they’re the ones who can do logistics and get people in and out and get things built.” In contrast to Gates, President Obama has emphasized that "the world is not doing enough" to fight Ebola.

The US response, according to Gates wasn’t late. "Was there some other government who took decisive action before we did?” he asked. “Was there a CDC equivalent who flew in and personally toured [the affected countries]?” WHO did not figure in his world. However, looking to the CDC as global sentinel—waiting for Tom Frieden’s trip report—further  delayed the international response several weeks. Frieden recently said "Speed is the most important variable here.” But for Gates, only Frieden’s trip revealed that: “even though the US and we had given money,” a reference to the foundation’s $1 million pledge, “that seeing the urban impact, that we really all needed to step up.” Frieden, unlike Gates, has said of the outbreak “this was preventable." But the trigger for Gates was anecdote from a top official, not epidemiology, reports from those on the ground, nor a WHO emergency.

It is not the CDC’s job to be the first-line monitor of international disease outbreaks, being neither not suited nor designed for it. Pointing out the obvious, a Lancet editorial noted “the US Government is not a multilateral health agency.” WHO, not the CDC, has an international surveillance network tied into national ministries of health in nearly every country. “The final responsibility to prevent the international spread of disease rests with WHO and IHR [the International Health Regulations],” the editorial concluded.

But whether one looks to the CDC or WHO, as the polio emergency demonstrates, both agencies toe the line set by the Gates Foundation. The foundation has downplayed Ebola, with Gates defending the timing and strength of the international response.

Gates’ “Big idea” on Ebola is to circumvent WHO to speed approval of experimental drugs: He asked: “Who decides that if there’s some slight increased risk of a side effect the benefits here outweigh that?” Legal authority and responsibility lie with WHO. A WHO panel of ethicists has already approved untested treatments.  But according to Gates, “It’s very tricky because really the world is not very practiced at what resources should come in and how these decisions should be made.”

Gates’ consistent answer to the world’s health problem remains: take away the functions served by the World Health Organization. He has been successful. Today WHO is timorous, enfeebled, and incapacitated, playing a mostly ceremonial, subservient role. Gates is protagonist. Ebola is out of control.

WHO Attacks Credibility of Suspected Drug-Resistant Malaria Case from Angola

[Note: See the latest developments here.]

The World Health Organization (WHO) rejects the findings of a paper describing suspected drug-resistant malaria in a Vietnamese migrant worker returning from Angola. (See previous post.) According to WHO's Pascal Ringwald, "It took 4 months for WHO to discover the truth and we will make sure that there will be retraction from the authors." But Patrick Kachur, chief of the Malaria Branch at the Centers for Disease Control (CDC), said "I doubt there will be a retraction," and that the CDC is going ahead with plans in Angola to search for similar cases and conduct tests on parasite clearance times.

Nearly all aspects of the case have been questioned. WHO has contended that the first line of treatment, artesunate, came from a batch recalled because of quality issues. The second line drugs, dihydroartemisinin and piperaquine, were delivered by nasogastric tube, a departure from preferred practice.  Also, the dose given, 1 mg/ kg given twice a day, achieves lower blood concentrations, according to mathematical models, than the recommended single dose of 2.4 mg/ kg once a day. The third line of treatment, quinine and doxycycline, were also delivered by nasogastric tube instead of intravenously as recommended. (Intravenous quinine was not available.) Still, nasogastric quinine worked, saving the patient's life. 

The apparent failure of the artemesinin-based drugs to clear the patient's malaria parasites has been attributed to hyperparasitemia which can impair clearance of parasites from the blood after they have been killed by the drug. Finally, genetic sequencing of the malaria parasites found them negative for K13, the biomarker associated with drug resistant malaria in Southeast Asia. 

The paper's authors have stood behind their research, refuting, for example, the claim that the artesunate used was of poor quality. But the battle continues. "Maybe," said WHO's Ringwald concerning the refutation. "But," when it comes to retraction, "CDC will," he continued.

All current containment efforts focus on Southeast Asia. The possible case from Angola threatens to expand an already fast-growing front, perhaps accounting for the heated debate.