By Dr. Kate O’Brien
Today is a landmark day, one that many global health experts thought might not happen. Today marks three years since the last case of wild polio in India, the requirement to officially certify the country, and with it the WHO South-East Asia Region, polio-free. While the official declaration is not due until March when a WHO Regional Certification Committee reviews all the data, today is a day to celebrate and to be remembered in India and around the world for years to come.
Photo Credit: Rotary International
It is a day to congratulate India, but also the global community. It is a day that gives us all strengthened hope and confidence in achieving the goal of global polio eradication. In 1998, India had a high of nearly 2,000 cases of paralytic polio from the wild poliovirus, and as recently as 2009, it still was home to most of the world’s polio cases. By 2011, it had wiped out wild polio cases, and now it has maintained that status for three years. India’s large, dense, and often migratory population combined with poor sanitation conditions in parts of the country created some of the most difficult conditions throughout the world to control disease. However, with a depth of commitment from all levels of government and civil society and dedication of significant resources, India achieved this mammoth goal. It could not have been done without the work of millions of individuals, including the 2.3 million vaccinators, the thousands of clinicians and epidemiologists in more than 33,000 surveillance sites, the religious leaders and advocates committed to on-the-ground outreach, and the leaders across government and industry who together contributed nearly US$2 billion in funding.
Thanks to all of these individuals, India is now polio-free, and its triumph over polio is a massive public health achievement---one that will leave a lasting impact on children's health in India and around the world. It is also a testament to the power of immunizations, which have been saving lives in India and around the world for centuries.
India has achieved a laudable reduction in global child deaths in recent years, and vaccines have been one of the most effective interventions in this effort. Not only have vaccines prevented deaths, but they’ve also helped children stay healthy and averted crippling social and economic costs to families and society. Beyond polio, India’s other great achievements related to vaccines are highlighted in this infographic.
Vaccines clearly work and they clearly work in India. As coverage levels increase and new vaccines are introduced into its Universal Immunization Programme, disease reduction will amplify, and children will lead healthier, longer lives. These inspiring efforts should be applauded along with India’s polio achievement.
India’s achievements should also inspire the global community to rededicate our efforts to ensure every child around the world is protected from preventable diseases. We have a unique window of opportunity to change history by eliminating polio from the three remaining countries where transmission has not yet been stopped – Pakistan, Afghanistan, and Nigeria – and maintaining disease control in other countries where elimination is fragile and polio threatens to return. With much learned from India’s success, communities, countries and the global community have a strong, actionable plan to achieve a polio-free world by 2018.
Ending polio everywhere, forever, is a critical step toward improving the lives of the world’s most vulnerable children. As India has clearly shown, polio eradication can lead the way for other child health initiatives, by strengthening surveillance systems, building networks of trained community health workers, and engaging leaders from across diverse disciplines. The job is not yet done; India and other countries around the world will need to sustain and continue to build on the progress to date while planning for the next step of introducing at least one dose of inactivated polio vaccine.
The remaining polio-endemic countries should have a deep sense of hope, bolstered by the accomplishments and lessons learned in India, that this goal is at their fingertips. The scientific, public health, communication, and organizational tools are in place. With the right political will, polio will be wiped out; there will remain substantial and at times unanticipated challenges to match the accomplishment of India in the remaining countries, but these are surmountable. There is a lot to be optimistic about. India has demonstrated to the world what is possible when the community in all its dimensions – local and global, political and religious, scientific and lay – has a common commitment. We call on all partners to continue without wavering the march toward worldwide polio eradication and in so doing achieve the purest measure of health equity.
Kate O’Brien, MD, MPH, is Executive Director of IVAC. A pediatric infectious disease physician, epidemiologist, and vaccinologist, she previously served as Deputy Director of IVAC. She also serves as Associate Director of the Center for American Indian Health.
Daniel Feikin, MD, MSPH
Special thanks to Daniel Feikin, MD, MSPH, for sharing his insight on his team’s latest publication. Dr. Feikin has been with the U.S. Centers for Disease Control and Prevention (CDC) for 15 years, where he spent 6 years with the Respiratory Diseases Branch and also served as the Epidemiology Section Chief for the International Emerging Infections Program in Kenya. Dr. Feikin has worked on a number of projects including surveillance establishing the burden and epidemiology of respiratory and diarrheal illness. Since 2010, Dr. Feikin has served as the Director of the Epidemiology team at the International Vaccine Access Center (IVAC).
Published in the September issue of PLOS Medicine, Serotype-Specific Changes in Invasive Pneumococcal Disease after Pneumococcal Conjugate Vaccine Introduction: A Pooled Analysis of Multiple Surveillance Sites analyzes the rates of invasive pneumococcal disease after the introduction of the seven-valent pneumococcal conjugate vaccine (PCV7). Dr. Feikin and colleagues from IVAC and CDC conducted this meta-analysis which showed that a reduction in all-cause and vaccine-type invasive pneumococcal disease happened rather quickly and was sustained for seven years after the introduction of PCV across the study sites. In the following interview, Dr. Feikin shares his insight on the issue of serotype replacement and how this it relates to decision making regarding PCV use.
What is serotype replacement (SR) and why is it an issue?
We have a unique situation with pneumococcus and pneumococcal vaccines with respect to serotype replacement. With pneumococcus, serotypes are defined by the kind of sugar capsule that surrounds the bacterium, and 90 different types have been defined. This creates a challenge for vaccines, which are based on specific serotypes. The first iteration of this conjugate vaccine could only fit in seven serotypes. They put the seven most common serotypes that you’d find in the US and Europe into the vaccine – that covered about 85% of the disease in the U.S.
First, SR was observed in the nose, which is where pneumococcus resides. Most of the time, the bacteria doesn’t cause disease, it just lives there in back of the nose (the nasopharynx) and a small percentage of the time, the bacteria in the nose will go on to cause an infection. When you get vaccinated, you get rid of the seven pneumococcal serotypes contained in the vaccine from the nose – quite effectively and quite rapidly. But what we also saw was that the seven serotypes that were wiped out by the vaccine were replaced by other serotypes of pneumococcus. That phenomenon – when you get rid of [serotypes] and they are replaced by others – is dubbed SR. The concern was: this is what happens to the bacteria living in the nose; does the same thing happen with disease caused by those bacteria? Are you just getting rid of the disease caused by the seven serotypes in the vaccine and having it be replaced by pneumococcal disease (PD) from the other serotypes? If that were to happen, you have the paradoxical situation of a vaccine that works against the seven serotypes you want it to work against, but your overall disease rates might not change in the long run because of SR. It was a really important question about whether this vaccine had an overall impact on disease – we needed to clarify whether SR exists and how much it exists.
What type of study did you choose to look at this issue and why did you feel it was the best way to research this question?
We conducted a meta-analysis, using 21 databases that were identified, to look at IPD rates after PCV7 introduction. When you are considering PD, you have to think about several different types of disease. The first type of disease is called invasive pneumococcal disease (IPD). IPD is the most straightforward because it means bacteria have invaded a normally sterile site – usually the cerebrospinal fluid, (the fluid surrounding the meninges) or the blood – and you can grow the bacteria from this fluid so it can be detected and positively identified. But the much bigger burden of PD is pneumonia, and most of the time when you have pneumococcal pneumonia you’re not going to isolate the bacteria since you can’t get a sample from the lung to grow and it normally isn’t a sterile site. So, when you want to look at SR, you are limited to looking at IPD – where you are able to culture the pneumococcus. That’s why the study focuses on IPD.
The second thing to understand is that there have been lots of individual studies from different countries, or different sites from the same country, that have looked at the issue of SR. There were many reports that came out after vaccine introduction and they were variable. There were some sites that showed very little SR and big impact of the vaccine. Then, there were other studies that showed up to full SR, meaning that you get rid of the vaccine serotype [with] full replacement by non-vaccine serotype (NVT), so in those sites there were no changes in overall disease rates.
This led to a lot of confusion. As countries in Africa and Asia were thinking about introducing PCV, they were concerned and somewhat confused about this issue of SR and wanted to know if PCV was worth their investment. That was the impetus in doing the study and it’s unclear why there were different results in different places. Some of it might have been that there truly was more SR in some sites, but it also could have been methodological differences or that some sites had very small samples sizes. One outlier site was potentially getting a lot of attention and people were looking at that saying there was complete SR, whereas another site was not showing that. So the idea behind the study was to put all the sites together, weigh all the studies according to their size and findings, and see if we could come up with some sort of summary of SR.
In the course of this analysis, was there anything that was surprising to you?
I have two answers for that. First, although a lot of countries had introduced PCV7, there weren’t many sites that had done the type of surveillance that we felt would be appropriate for this type of analysis. There were sites that were doing surveillance, but when you boiled it down to who met stringent criteria for being able to evaluate SR, there weren’t as many as I thought. That was a lesson because people are out there publishing studies and making conclusions about SR with limitations in their surveillance, which we felt would affect their interpretation of SR, so we did not include those types of studies. We were fairly rigorous in our inclusion and exclusion criteria, so we only ended up including 21 studies.
The second thing that was somewhat surprising to me in the results was that when we looked at children, and when we looked at the overall impact of this vaccine on children, there was about a 50% reduction in overall IPD. So, overall IPD decreased by half. We saw that decrease happen by the first year after the vaccine was introduced and it stayed at roughly 50% reduction all the way out to about seven years. I thought that initially there would be a growing reduction in overall PD over time. The drop in the first year was greater than I thought – suggesting that this vaccine had a pretty fast impact on pneumococcal epidemiology in children – and it didn’t change a lot after that first year. Now, there was a lot going on with each progressive year, so vaccine types started to go down and they continued to go down out to seven years until they were virtually gone. You were getting a lot of change in the different serotypes starting in the first year after vaccine introduction and continuing out, but changes in the vaccine types and changes in the NVTs balanced each other out, so this overall 50% reduction remained fairly consistent over the seven years.
How could this study contribute to policy making?
I think that for policy makers (people that don’t think about PD everyday), I think their take-home point is that there’s about a 50% reduction in IPD in children and it lasts all the way out to seven years. There is SR; it exists. It’s a real phenomenon, but the proportion of disease caused by vaccine serotypes is greater than non-vaccine serotypes, so the vaccines do have an overall impact on disease in children. I think that’s the first message.
The second is that you do see a herd effect in adults. There is a decrease in overall IPD in adults. It’s not as great as what is seen in children and it’s a bit delayed, but at least in the countries that introduced PCV, there was herd protection among adults – which could potentially have a big impact for countries, especially low-income countries, that have a lot of PD in adults. For a decision maker, hopefully that’s the message they get from this.
Are there any plans that you know of to build on the evidence provided by this study, and investigate SR in higher valency PCV?
There are some clear limitations to this study. The first limitation is that this study looked at the impact of the 7-valent PCV. That vaccine is no longer made. Countries are introducing either 10-valent vaccine or 13-valent vaccine. Much of the SR that we saw occurring came from the six extra serotypes that were not in the 7-valent vaccine but are now in the higher valency vaccines, so we suspect that these higher valency vaccines would take care of a good deal of the SR that we saw.
What we don’t know is: Are there other serotypes that are waiting in the wing that will cause SR in the same way? It would be important to follow countries as they introduce the higher valency vaccines and do a similar type of analysis several years out after the vaccine has been introduced. The problem is: we showed that you really need to go out to five or more years after vaccine introduction to see what exactly is going to happen to this dynamic process overtime. You can’t do the studies yet because the vaccines have just been introduced in the last couple of years so we need to wait, particularly for developing countries because they are just introducing.
The second major limitation is that the studies we looked at in our analysis were mostly from developed countries (North America, Europe, and Australia). There were a few indigenous populations in our data set – the Navajo and the Australian indigenous – which might be more like the low-income country populations, but not exactly the same. So, it is possible that in Africa and South Asia, where the epidemiology of PD is different, the results of the vaccine could potentially be different as well. It would be important to do a similar type of analysis in those countries. I think this type of analysis needs to be repeated in a few years, and it needs to be repeated in low-income settings that have the higher valency vaccines.
Do you have any other thoughts that you want to convey that we have not covered?
I think there is one thing, not based on the data itself, but just a comment. One of the things this study showed is the power of collaboration. Any single site would not be able to do this type of analysis, but they showed data from their own site and they made conclusions for their own site. But in order to understand an epidemiologic concept in a broader way that may vary site by site, you really need to have data from different places. The willingness of investigators to collaborate on this project, to lend their data to be looked at, to work together to make some sort of conclusion that was bigger than their own data was a really valuable exercise. This type of collaboration between sites is becoming more and more important, and we’re seeing more of it happening in the field of epidemiology. So, the example of doing a multi-site analysis, where sites give their data and they participate in the interpretation, was a valuable lesson and exercise.
By Lois Privor-Dumm and Bruce Lee
You are having 100 guests for an outdoor picnic and need to make the decision: do you buy big bottles of soda (potentially messier but less expensive), smaller bottles (potentially more convenient but also more expensive), individual cans, or a compromise between the two? Your decision will depend on several factors including available refrigerator space, price, convenience, expected number of guests, and probability of leftover soda. You may also consider the servers (adult or child), the risks (e.g. mess, amount consumed) availability (will there be enough, is there a need to ration?), and waste produced (e.g., aluminum cans versus plastic bottles).
Sound familiar? It’s a very similar decision process for vaccines – which must consider the price to the country, if there is enough storage space, how difficult is it to transport all of the required product to where it needs to be, how much wastage will there be, if is there enough for everyone, and what is the risk that some containers will remain unopened?*
Looking at shelves in a grocery store, it is clear marketers understand the dynamics of these everyday decisions. Companies like Coca-Cola fully research how consumers make decisions and weigh trade-offs of price, size, and convenience. They vary offerings by region and by store, limiting choice in some places and providing every option under the sun in others.
Interestingly enough, where the stakes are very high – in vaccines – there doesn’t seem to be the same level of consideration. No one gets sick if a bottle of Coke is not available. We wish the same were true with a vaccine. Yet countries, donors, and manufacturers often do not fully weigh the consequences of container choice on cost, availability, likelihood of usage, and safety.
IVAC’s new report, Coverage, Cost and Safety Impacts of Primary Container Choice, details these tradeoffs and calls on the public health community to take a more data-oriented approach to supporting decisions for each individual vaccine. The report uses various scenarios run on the Highly Extensible Resource for Modeling Supply Chains (HERMES) model of the Benin vaccine supply chain built by the HERMES Logistics Modeling Team, working with colleagues from the Logivac Project and Benin. The HERMES Benin model allowed us to change the size of a vaccine container and simulate the resulting effects (e.g., cost per dose delivered and vaccine availability). The effects depend on a number of factors, including other vaccines in the supply chain, current constraints, and wastage policies (e.g., is a vaccine vial opened or not depending on number of children in a session).
We also considered what could happen at particular locations and clinics...not just at the country or global level. This is important since country-wide measures of routine vaccine coverage may be misleading. Often, country-wide routine vaccine coverage is high (>90%) even when coverage in remote areas (where vaccines are needed most urgently) remains low. Remote areas also may be very difficult to reach, have limited refrigerator space to store vaccines, and offer poor access to health care, all resulting in limited vaccine availability and high disease risk. At the same time, fewer children may show up to be vaccinated on a particular day, making healthcare workers loath to open a vial if they want to avoid wasting unused doses and country policies may compel them to do so. There is also an additional scenario to be considered for countries or even communities that are risk averse. Some product presentations inherently carry with them an increased risk for contamination (particularly multi-dose vials if not handled appropriately) or error (e.g, when a lyophilized vaccine is reconstituted with product other than diluent), or even contain a preservative that may be perceived to have safety issues (as is the case with thiomersal in some high- and middle-income countries). In this scenario, containers not requiring preservative or single-use presentations may be preferred, even when space is limited and/or cost may be higher.
At a global level we must start looking at the unique characteristics of each new antigen, providing guidance well in advance of product introductions, and looking across a range of scenarios. Although it is tempting for the manufacturer to limit the number of product presentations, building a case based on simulation experiments from a variety of countries, considering implications on coverage, cost, safety, and feasibility could help manufacturers better understand the investments needed and the “cost” of getting it wrong. Furthermore, the global community can better appreciate why certain costs may be higher for some populations and evaluate the need for more specific guidance on individual vaccines across a variety of scenarios. Container choice is not as straight forward as looking at price, wastage, and space. When humans are involved and there are imperfect choices, we should be approaching the decision with a framework that considers global, local, and manufacturing implications to make better-informed choices for every product introduced.
A number of efforts are underway that have improved forecasting and enabled a more systematic view of cold chain space. Now is the time to invest in ensuring we understand the full picture of cost per dose delivered, availability, and safety for each individual product and scenario to make better informed decisions.
*When there is a mismatch between number of doses in a vial or container and expected session size (e.g. the health worker sees two children per day and has a 10-dose vial of vaccine) and there is concern about wastage or availability of vaccine for future sessions, some health workers may not open the vial and vaccinate those children that particular day. The multi-dose vial policy, which enables the vaccine to remain opened for a designated period of time, can help mitigate wastage concerns, but it isn’t always followed, and not all vaccines are eligible.
Lois Privor-Dumm, MIBS, is Director of Policy, Advocacy & Communications and Bruce Lee, MD, MBA, is Director of Operations Research at IVAC.
By Dr. Dagna Constenla and Samantha Clark
For many people throughout the world, the bite of a mosquito is nothing more than a common annoyance. But for individuals living in dengue endemic countries such an annoyance can quickly turn into a life threatening condition. Patients who get sick with dengue fever often experience excruciating headaches, skin rash, and debilitating muscle and joint pains. In severe cases, it can lead to circulatory failure, shock, coma, and death. Though early and effective treatment can ease symptoms, there is no specific cure available for dengue. Efforts to control dengue through preventing mosquito bites and breeding have proven to be largely ineffective due to the mosquito’s tendency to feed throughout the day and ability to breed in even small bits of stagnant water.
The good news is a vaccine is forthcoming. After more than 60 years, the development of dengue vaccines has accelerated dramatically. Today, several vaccines are in various stages of advanced development, with clinical trials currently underway on five candidate vaccines. While it is difficult to predict the introduction date of a new dengue vaccine, it is expected that one will be available by 2017.
Unlike a new iteration of an existing vaccine, this is uncharted territory. Even if a dengue vaccine is successfully developed, a number of issues remain. How do we predict its use? Its costs? Its cost-effectiveness and affordability? How will countries introduce it?
Perhaps the greatest challenge facing countries will be how to finance the addition of a dengue vaccine to the national vaccine schedule. Vaccine price, availability of funding, and ability to negotiate pricing will all play a critical role in the ability of a country to finance a dengue vaccine. In the Americas, one of the regions where dengue is endemic, a key mechanism for introducing new vaccines has been PAHO’s Revolving Fund. This, along with other options such as pooled procurement, regional and domestic taxes, and low interest multilateral loans are all potential sources of funding.
These and other funding topics will be on the agenda at a workshop starting today and hosted by IVAC, a core partner in the Dengue Vaccine Initiative, in partnership with the International Vaccine Institute, the Sabin Vaccine Institute and the Pan-American Health Organization. The dengue finance workshop will bring together more than 30 experts from the Latin America and Caribbean region, including academics, representatives from bilateral organizations, international public health agencies, nonprofit organizations, international financial institutions, and government agencies. They will convene in Washington, D.C. on July 22-23, 2013 to discuss the challenge of vaccine finance in countries throughout the region.
This workshop will be critical to laying the groundwork for countries to establish a viable financing plan that can be immediately implemented following the introduction of a dengue vaccine. Stay tuned to the IVAC website for more information following the workshop.
Dagna Constenla, PhD, is the Director of Economics & Finance at IVAC. Samantha Clark is a Health Economist at IVAC.
By Dr. Kate O'Brien
While the political turmoil and violence in Mali occupied headlines earlier this year, we here at IVAC were acutely aware of the situation as we worried daily about our partners there, including Dr. Samba Sow and his team at Center for Vaccine Development (CVD) in Bamako, who lead the Mali site of our Pneumonia Etiology Research for Child Health (PERCH) project. Earlier this month, our team had a chance to return to Mali, now that the situation in the capital has stabilized. We were impressed at CVD’s ability to keep the PERCH project – not to mention their work on the Global Enterics Multi-center Study (GEMS), MenAfriVac, and a few other randomized vaccine trials – up and running during the crisis, and to make the right choices to safely balance the security of their staff and care for patients while maintaining the integrity of the research. The trip got me reflecting on the broader efforts around pneumonia prevention, and three things struck me as worth sharing.
Kate O'Brien with members of IVAC's PERCH team and CVD-Mali in Bamako.
First, in spite of the progress on PCV, our work is not done on squelching the burden of pneumonia and the problem is not being fully met with the resources needed to tackle it. Much time and many resources are being allocated to global mortality estimates, including for pneumonia, and there is evidence that this burden of mortality has fallen meaningfully over the past decade. Credible disease burden efforts have an important place in the global health landscape and deserve to be done, and done properly, but they are, and will always be, a monitoring and planning tool. They only reflect the progress; they are not the progress itself. These estimates are fully dependent on sound, high-quality fieldwork on pneumonia burden, and the consequent efforts and research on protection, prevention, and treatment of pneumonia. There is too little funding for strategic fieldwork on pneumonia. Being in Bamako, in the hospital, in the clinic, and most importantly visiting communities and households of families who are affected by pneumonia, reminded me that this is where progress is made and this is where we must invest and innovate.
Second, we have to focus on what will meaningfully make changes in the burden of and mortality from pneumonia. We still don’t have tools that can readily differentiate the children with true pneumonia from those with other lower respiratory diseases that require a different treatment. Families still don’t have the basic understanding of signs of respiratory disease for which they should readily seek care. And hospitals and clinics remain crowded, under-resourced, and fragile with treatment approaches that too often are unable to support children through their illness. This is why children die from pneumonia, still.
CVD-Mali staff demonstrate procedures as Kate O'Brien and other PERCH team members observe.
Third, there are field research sites that have built expertise, infrastructure, and experience to tackle the important unknowns, but they are fragile and will not remain unless investments are made. In spite of the constraints, there is research of the highest quality ongoing in places where child mortality from pneumonia is highest, including in Mali. It is outstanding how the CVD-Mali team managed to keep all of its critical research projects up and running not only through the day-to-day challenges, but also through the political challenges of this past year. It was a great honor to learn from them, to work on solving challenges at the site, and to renew our understanding of where focus and effort is needed to make reductions of pneumonia and diarrhea a reality on the ground, and not just in our computer algorithms and spreadsheets.
Kate O’Brien, MD, MPH, is Acting Executive Director of IVAC. A pediatric infectious disease physician, epidemiologist, and vaccinologist, she previously served as Deputy Director of IVAC. She also serves as Associate Director of the Center for American Indian Health.