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 Dr. Samba Sow
Dr. Samba Sow is Director General of the Center for Vaccine Development – Mali (CVD Mali) and a Professor of Medicine at the University of Maryland School of Medicine. This blog is cross-posted from Lancet Global Health.
Scientific research, by definition, is about process. Scientists must follow carefully developed guidelines and established protocols to make sure research is conducted validly, accurately, and ethically. As any field researcher knows, meticulous attention to detail is challenging at the best of times, when obstacles like staff turnover, equipment shortages or delays, power outages, strikes, security concerns, and disruptive rumours are not out of the ordinary. But these “everyday” logistical challenges of doing research are further compounded when political instability surrounds your research site.
In the past year, my colleagues and I at Center for Vaccine Development (CVD) Mali faced immeasurable challenges in keeping research efforts going when the insurgency that has afflicted our country for decades began moving southward and threatening the capital city of Bamako, where our research centre is located. Read the full blog at the Lancet Global Health.
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.
By Dr. Kate O’Brien
This week scientists came together to declare that we will eradicate polio in 5 years. It’s an achievable goal, and admittedly an aspirational one. But, if we as a global community leverage proven strategies and follow through on commitments made, it will be met. It is amazing to think that this goal, which just two decades ago seemed impossible to many, is now firmly in our sights. It also gives me confidence that we can reach other goals, such as reducing preventable childhood deaths to a degree that any such death is seen as a shocking, rare event rather than predictable and intractable. This challenge, which the global health community laid out in last year’s Promise Renewed initiative may seem daunting, given that despite recent declines, 6.9 million children died in 2011. However, when you consider that worldwide polio cases have dropped by 99% since the Global Polio Eradication Initiative began in 1988, it is clear these problems are surmountable. Like polio eradication, we need a concrete approach to tackling the leading child killers, and we made a big step forward with today’s launch of the Integrated Global Action Plan for Prevention and Control of Pneumonia and Diarrhoea (GAPPD). Released by WHO and UNICEF, GAPPD clearly outlines the steps we must take to eliminate the two leading killers of young children in 20 years.
The Integrated Global Action Plan for Pneumonia and Diarrhoea (GAPPD)
Most of my professional life has been spent assessing and applying interventions to reduce pneumonia and diarrhea, both in the United States among American Indian communities and around the world in the communities where most child deaths still occur. I’ve seen the burden of these diseases in the numbers we calculate and on the faces of the patients I’ve treated. I’ve also seen that we have the tools we need to stop children from dying or suffering from severe pneumonia and diarrhea. When I worked in Haiti, the ward was full of children, over a third of whom would die in those beds. Nearly all of the illnesses these children had were fully preventable, mostly through the use of vaccines but also through other simple, sensible interventions. The interventions we have work, and the task we have is to figure out how to use them most effectively, to know if what we are doing is working, and to make adjustments in optimizing their impact. This feedback loop can only be put in place when we can measure the impact of what we’re doing. We may not be able to measure with absolute precision, but with enough precision to know if our time and treasure is being wisely spent.
We know what we need to do to tackle pneumonia and diarrhea, and establishing clear evidence on the burden of disease and on interventions that work creates the platform from which we can prioritize our efforts. A new series published in the Lancet today in conjunction with GAPPD provides updated evidence on this front. One of the papers, led by faculty in our Department of International Health at Johns Hopkins provides updated mortality estimates for pneumonia and diarrhea – together responsible for more than 2 million child deaths in 2011.
We also have a clear understanding of which interventions work, and we know that many of them overlap. As my colleague Bob Black pointed out in the Lancet series launch, while diarrhea and pneumonia have very different symptoms and causes, several risk factors for the two diseases are the same, including under-nutrition, suboptimal breastfeeding, and zinc deficiency, meaning that they can be effectively prevented and treated as part of a coordinated program. We also know that vaccination campaigns will play an important role. A second paper in the Lancet evaluated 15 key interventions using the Lives Saved Tool. It found that nearly one third of severe diarrhea episodes could be prevented by widespread vaccination against rotavirus and cholera, while up to two thirds of pneumonia deaths could be prevented by implementation of pneumococcal and Haemophilus influenzae type b vaccines. With ambitious scale-up – 80% coverage or more – the authors estimated all 15 interventions could effectively eliminate (95% prevented) diarrheal deaths and prevent around two-thirds of pneumonia deaths by 2025. All this at a total cost of just USD6.7 billion.
GAPPD and the Lancet series reflect years of work toward a consensus among all stakeholders that we must target our efforts on proven interventions, and we must work together in an integrated way. Many of the interventions for childhood diseases overlap, and can be delivered more efficiently if all parties work together. This integration will not only result in better care for each child, it is also crucial in resource-poor settings, where countries simply cannot afford to maintain siloed efforts and where partnering countries and organizations are increasingly demanding more impact for their investments.
We have the evidence, and our marching orders are clear. With polio eradication beckoning our efforts, it is the time to leverage this energy, know-how, and confidence by fulfilling our promises and advocating for all stakeholders – donors, governments, civil society, and other leaders – to fulfill theirs. We can all take inspiration and insight from polio eradication efforts and make the end of preventable pneumonia and diarrhea deaths a reality.
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.
By Dr. Juliet Otieno
This the second blog in a series from the Pneumonia Etiology Research for Child Health or PERCH study team. PERCH is a multi-country case-control study of the etiology of severe and very severe pneumonia in children aged 1-59 months. Led by IVAC and funded by the Bill & Melinda Gates Foundation, PERCH operates seven research sites throughout Africa and Asia.
As a Kenyan doctor, having completed my internship at a rural mission hospital and worked as a junior doctor in a paediatric hospital for just over a year, I found myself two years ago in a small rural town, Kilifi, in the heart of a study on the causes of childhood pneumonia, the Pneumonia Etiology Research for Child Health or PERCH. When I began working with the PERCH study, a study on the “causes” of pneumonia initially seemed to me as a rather counter-intuitive approach to the problem at hand. I had spent years cramming the national diagnostic and treatment guidelines for pneumonia and I was pretty confident in the management of children with acute and chronic respiratory illnesses. I did not need the much-cited research to know what pneumonia looks like or to understand its burden on our children.
Physicians from three different PERCH sites, Dr. Juliet Otieno, Dr. Bernard Ebruke, and Dr. David Moore, examine a chest x-ray of a patient with pneumonia during a cross-site visit in South Africa.
Childhood pneumonia is a topic I have always been able to easily relate to, starting from my days as a medical student in the busy paediatric wards where most of the very sick children had respiratory illnesses. While efforts have been instituted to ensure early recognition and treatment of children with pneumonia, unfortunately a child succumbing to death from a respiratory illness is still seen as an unfortunate but inevitable eventuality in most of our hospitals in Kenya.
Two years later, I have had many epiphanies along the way about the importance of investigating the causes of pneumonia, but a recent one has been particularly influential and has changed my mindset completely. I recently had the opportunity to attend a cross-site visit to Chris Hani Baragwanath Hospital in Johannesburg, South Africa – another PERCH study site – where I had a chance to look at a histopathology slide of lung tissue from a child who died of pneumonia. Post-mortem lung biopsy studies are carried out as part of the PERCH study in some of the participating sites because they can give researchers a much more direct, accurate diagnosis of etiology in fatal pneumonia cases. (Learn more in this 2011 article in Clinical Infectious Diseases.)
This particular post-mortem lung specimen we were examining was from a child who presented with clinical features consistent with pneumonia caused by pulmonary tuberculosis and was treated for this condition without success and died. The post-mortem analysis revealed that the child did not have TB, a bacterial infection, but instead the pneumonia had been caused by florid cytomegalovirus infection, a virus that spreads through bodily fluids and is especially dangerous for patients with compromised immune systems. If the doctors caring for him had known this, they would have treated him differently, and he might have lived. Unfortunately, we cannot get such an accurate picture of the pathogens present in the lung with current tests available for patients. It dawned on me just then how important post-mortem results are in defining the epidemiology of pneumonia in a particular setting, made possible through studies like PERCH, and which help doctors see the range of pathogens that are causing child deaths in their hospitals, so they might be more aware and ready to treat them.
I left wondering what definitive pathogens we would find if we carried out post-mortem studies on fatal pneumonia cases in Kilifi, and how this would influence our clinical management of pneumonia. Would we only find the “traditional” bacteria we expect? Or would we be opened to a whole new world of “atypical” bacteria that we occasionally treat as a last ditch resort? Would we see that the recently introduced vaccine against the streptococcal pneumonia bacteria caused a significant reduction in one of the most common “traditional” pneumonia-causing bacteria? Would our very definition of “atypical” pathogens be challenged? Would we be more confident in administering relevant antimicrobial treatment – albeit a non-conventional approach – in a more timely manner? I also wondered how post-mortem findings would compare to the induced sputum test results we gather through PERCH, which get us as close as we can to the lung while the child is living, but are still unproven, and leave us wondering if we’re really getting at the source of the infection. Most importantly, I wondered if all this knowledge could be the answer needed to save lives, reduce unnecessary use of antibiotics that can lead to resistance, and decrease the burden of pneumonia morbidity in our paediatric ward?
Dr. Otieno demonstrates a nasopharyngeal swab during a training session.
At a clinical level, results from post-mortem studies are easily interpretable and could improve the outcome of pneumonia cases at our hospital. At the same time, they are often difficult because they require gaining consent from a grieving parent. But because I now understood the value of post-mortem studies in protecting all our children from fatal pneumonia, I went home with a stirring in my heart to test the waters of community acceptance. I was reminded of a common saying, “better the devil you know than the devil you do not know,” for despite the challenges associated with post-mortem studies, knowledge of the bugs causing pneumonia today would give us the best chance at saving lives in the future, rather than continuing to treat what we don’t know or what we only think we know.
I am grateful for the opportunity to visit another PERCH research site in South Africa and learn from my colleagues across the continent. I come away from the experience having realized that the value of postmortem analysis in pneumonia etiology studies cannot be understated. Working in this multi-site project has brought back the nostalgia of my internship year, including the steep learning curve, but also the accompanying fulfillment at the end of each day.
I also have a deeper appreciation that the PERCH study is indeed a landmark study. Working on this project has been an exciting experience and has given me the unique opportunity to be part of the global effort to protect millions of children around the world from pneumonia, and it has shaped my career trajectory towards pneumonia prevention strategies.
Juliet Otieno, MD, is a Clinical Research Training Fellow at Kenya Medical Research Institute (KEMRI) Wellcome Trust Research Programme and a member of the PERCH study team.