Category Archives: Vaccine

Pneumonia and Malaria – similar challenges and pathways to success

ConcentrationOfPneumoniaDeathsWorld Pneumonia Day (WPD) helps us focus on the major killers of children globally. While Pneumonia is responsible for more child mortality across the world, in tropical malaria endemic areas both create nearly equal damage (see WPD graphic showing Nigeria and DRC which are both have the highest burden for pneumonia, but also malaria). Of particular concern is case management at the clinic and community level where there is great need to differentiate between these two forms of febrile illness so that the right care is given and lives are saved.

WPD_2014_logo_portraitDiagnostics are a particular challenge. While we now have malaria rapid diagnostic test kits that can be used at the community level, we must rely on breath counting for malaria. The Pneumonia Diagnostics Project (see video) “is working to identify the most accurate and acceptable devices for use by frontline health workers in remote settings in Cambodia, Ethiopia, South Sudan and Uganda.”

Ease of use at low cost must be achieved. One approach to solve the pneumonia diagnostics challenge at community and front line clinic level is to find “mobile phone applications or alternative energy for pulse oximetry,” to test low oxygen levels.

PneumoniaCareVaccine development for both diseases is underway. The challenge for malaria results from the different stages of the parasites life-cycle. Lack of affordable vaccines for pneumonia limits at present widespread preventive action, though public-private partnerships offer hope.

Dispersable and correct dose for age prepackaged malaria drugs are already available. Now more child-friendly medicines for pneumonia are being developed. In low resource settings, “amoxicillin dispersible tablets are a better option, particularly for children who can’t swallow pills. They have a longer shelf-life, are cost-effective, don’t need refrigeration, and are easy to administer.”

Similarities in the problems and solutions to control these two diseases require that interventions must continue to be developed and implemented jointly in order to benefit children the most. As can be seen again from the WPD graphics (right), many children do not get needed treatment. Integrated case management at all levels is the answer.

Effective does not mean realistic – the challenge of malaria vaccines

“This is a scientific advance rather than a practical one,” said Dr. William Schaffner, of Vanderbilt University’s Medical School to the New York Times. So goes the fate of the latest in research reports on efforts to develop a malaria vaccine.  Prof. Schaffner goes on to explain that, “Giving multiple IV doses of any vaccine is also impractical because it requires sterile conditions, trained medical personnel and follow-up. IV drips are particularly hard to administer to children.”

It seems that every possible media outlet in the planet picked up on the fact that this intravenous dose of irradiated/killed malaria parasites was 100% effective. Most though did not see this as just one more step in understanding the long string of immunological research processes needed to come up with a vaccine that can actually work under real life field conditions.

recent-dhs-reports-on-child-immunization-coverage-sm.jpgJust last year, hopes crashed on a long-tested malaria vaccine known as RTS,S that had been through clinical trials in several African countries.  Not only did the vaccine need to be administered three times, but even then achieved limited effectiveness, though severe malaria appeared to have been reduced by around 50%. Just last year unfortunate results from monitoring showed that over time the vaccine lost the effectiveness it initially achieved.

It had been hoped that if this or another successful vaccine candidate could be ready for scale up, that it could be integrated into the existing child immunization programs of malaria endemic countries. Findings from recent Demographic and Health Surveys shown here remind us that even vaccines that have been routinely delivered to children for decades still have problems achieving adequate coverage.  Two of those depicted, DPT and Polio, like the RTS,S required three doses. This is a logistical and management challenge to be sure, but also a social, cultural and behavioral one.

The vaccine search goes on with several research reports appearing monthly on new findings about human immune responses to malaria in it various forms.  We trust that one day a vaccine that is effective as the existing child immunizations will come to market. Even then, as we can see from ‘normal’ vaccine coverage rates, we will not be able to rely totally on a malaria vaccine for preventing the disease. Of course none of the existing preventive measures reaches all people, and hence our malaria elimination strategies must continue to include a combination of approaches.

TB setbacks: lessons for malaria control

Tuberculosis is one of the big three receiving Global Fund support, and like HIV and malaria control efforts, the emphasis is on multiple interventions to ensure ultimate success. Compared to the other diseases, TB’s interventions have been mainly limited to immunization and directly observed treatment. Both of these interventions have recently met some major challenges that have also plagued the other big diseases.
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Roger Bate and colleagues, who have focused on the problems of fake and substandard malaria drugs have turned their attention to TB. (see http://masetto.ingentaselect.co.uk/fstemp/a5829970064042ab6ec12023d514ef4f.pdf ). Their investigation at pharmacies in 19 Asian and African countries found around 9% of TB drugs were substandard/poor quality. The rate of fake medicines was 16% in Africa and 10% in Asia.

Governments in these countries were encouraged to give these issues greater attention including better regulation and collaboration with international policing efforts.

The need for new vaccines is a necessary development to maintain a strong disease control arsenal. For TB, “A new vaccine, modified Vaccinia Ankara virus expressing antigen 85A (MVA85A), was designed to enhance the protective efficacy of BCG.” (as reported in The Lancet http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2813%2960177-4/abstract )

As the BBC report on this study pointed out, “BCG is only partially effective against the bacterium that causes TB, which is why several international teams are working on new vaccines.” (see BBC at http://www.bbc.co.uk/news/health-21302518 )

While the new vaccine “… was well tolerated and induced modest cell-mediated immune responses. Reasons for the absence of MVA85A efficacy against tuberculosis or M tuberculosis infection in infants need exploration.” Fortunately research on other vaccine candidates is underway.

Continued control and eventual elimination of malaria and TB will require research that is both basic (vaccines) and applied (drug quality) in order to develop, maintain and implement effective strategies. Disease research budgets should not be compromised in the ever changing world of pathogen/parasite evolution.

Vaccines – tried and true or tired and blue

The March 2013 issue of Discover Magazine provides a chilling overview of why a standard vaccine against pertussis (whooping cough) is no longer as effective as we hoped. About 20 years ago the US switched from killed whole bacteria vaccine to one that contained five key proteins. The change was necessitated by some severe reactions to the original vaccine. http://discovermagazine.com/2013/march#.URdn-2fn_1k

who-208327-ethiopia-pvirot-sm.jpg [PVirot, WHO Ethiopia 2002.]

It has come to light that the effects of the current pertussis vaccine, given in combination with tetanus and diphtheria immunization (DPT) last only a short time, as little as one year for adults receiving the booster. It seems that the five chosen bacteria proteins may have evolved and that those in the vaccine confer less immunity.

There are efforts to find new adjuvants to enhance efficacy, but what we are witnessing is a constant battle for balance between finding both safe and effective health interventions. http://www.ncbi.nlm.nih.gov/pubmed/23291942

Why should malaria program people be concerned about pertussis? Recent trials of the new RTS,S/AS02D malaria vaccine is that research trials of this new malaria tool were designed to integrate it into existing childhood immunization programs, including DPT. Not only are we concerned about whether the malaria vaccine works, but whether there might be any negative interactions with other concurrent vaccines. http://www.ncbi.nlm.nih.gov/pubmed/23297680

Community members may not easily distinguish all the different diseases in a vaccination program, but the success or failure of any one component may affect their attitudes to the whole package.

In the case of malaria, an effective vaccine that guarantees more protection than those currently under trial, will be important tools in efforts to control the disease. Vaccines may not yet provide the key to elimination. Also as we can see, vaccines that were once effective may loose their edge, much as parasites and vectors may develop resistance to medicines and insecticides. That is why program managers must always ensure adequate resources for a multi-intervention approach.

15 Months, 46 percent – prospects for malaria vaccine

Researchers on the new RTS,S/AS01E malaria vaccine have extended the follow-up period on the children who had received the vaccine in Kenya and Tanzania and the vaccine which had offered 53% protection against malaria at 8 months, continued to be protective, though at a slightly reduced rate of 46% at 15 months.

cph-immunization-sm.jpgPeople who bet may not like those odds, but the key to understanding this vaccine, which is likely to be the first into the public health system when final trials are over, is the nature of the actual effect. While the vaccine does not prevent the occurrence of malaria in most recipients over the long haul, it does prevent life threatening severe malaria including cerebral malaria and severe anemia – factors that contribute to malaria mortality.

The public health challenge going forward is three-fold (at least). The first challenge will be affective delivery of the vaccine though national immunization programs, which have had trouble keeping up with coverage of the routine immunizations like DPT and measles.

The second is convincing the public that a vaccine that does not completely prevent malaria in all children is worth their effort to get imminuzed. This is compounded by local perceptions that any fever might be malaria, and as we know there are many viral and bacterial causes of fever co-existing in the same environment and children as malaria. The vaccine will prevent malaria to an extent, but not preent fevers. This chalenges out ability to communicate.

The third challenge is how one should combine vaccination with prompt and appropriate case management (diagnosis, treatment and counseling) for those who do get malaria after the full regimen of the new vaccine.  This tests the oft stated premis that a vaccine is not a magic bullet, but part of a package of control interventions. One also hopes that people trust the vaccine to the extent that they abandon their insecticide treated bednets.

The battle for a malaria vaccine just begins when the research trials are finished. It is at this point where the human element, represented by health systems managers, community leaders and health consumers, need to be considered.  If this were a new soft drink or cell phone product facing the effectiveness and efficacy challenges described above, one could forgive investors from being wary.  In this case we cannot afford to be overly cautious investors when children’s lives are at stake.

Can We Simplify Malaria History?

Scientific American is known for making the latest scientific advances – from dark matter to disease management – accessible to a wide audience.  An article in the November 2010 issue on malaria vaccine progress is generally a good example. The following passage though, may simplify the history of eradication a bit too much.

In the 1960s an enormous campaign wiped out the disease in many parts of the world and drove down its number in others. But that success ultimately bred its own end. As malaria became perceived as less of a threat, global health agencies became complacent; their chief tool, DDT, was found to be toxic to birds, and they largely abandoned their efforts. Malaria numbers roared back more fiercely than before.

sciam-mal-vaccine-research.jpgTwo specific issues from the foregoing do not paint the full picture. First, bird deaths did not stop malaria eradication, though the toxicity issue is true in its own context. The real end of DDT was bred by mosquitoes developing resistance to the pesticide, which was discerned even before the campaign reached its height. The Lancet in reviewing Randal Packard’s book, The Making of a Tropical Disease, a Short History of Malaria, explained that …

It (the eradication campaign)was far too monodimensional, relied too much on DDT spraying, and neglected the palpable problem that the delivery infrastructure was not in place in too many parts of the malarious world. The emergence of widespread mosquito resistance to DDT, and parasite resistance to the cheap mainstay of therapy, chloroquine, compounded the difficulties.

Secondly, at least for colleagues in the US Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO), malaria research overall did not halt. Surely the funding levels were not as high as we see today, but persistent research provided us with new tools including insecticide treated bednets, artemisinin-based combination therapy, and nearly a dozen insecticides for indoor residual spraying, for which we are thankful.

True, these additional tools do not confer permanent immunity as a vaccine eventually should, but their implementation has driven down the number of malaria deaths in many countries, and when a vaccine comes along to strengthen the toolkit, we will be farther down the long road to elimination. The malaria lifecycle is complex, and health systems designed to deliver malaria interventions is equally complex (and challenging), which means we cannot  and should not expect a magic bullet in the near future.

As Randal Packard pointed out a key lesson from the first eradication campaign needs repetition, lest we again blame it all on the birds. Aside from developing insecticide resistance, there was clear indication that the health systems in the most highly endemic areas were not able to maintain continuous IRS application.

Health systems are stronger today, due in part to recognition by partners (international and internal) that malaria cannot be controlled, much less eliminated, without health system strengthening. It is these same health systems that will also be required to deliver the new malaria vaccines, so they better be strengthened before vaccines are rolled out.

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Another short note of concern about the Scientific American article – in a box entitled “Plan B: Vaccine Alternatives” we are correctly shown that the effort to eliminate malaria has other tools that must be sustained. Unfortunately the text refers to malaria as a ‘virus’, though elsewhere in the article the stress on ‘parasite’ prevails.

Vaccines – an end and a beginning

Polio eradication efforts are pushing toward the end. The New York Times, in discussing setbacks in the mostly successful eradication effort such as outbreaks in Tajikistan and emergence of a mutated attenuated vaccine virus that has caused some cases, stressed the importance of ‘more aggressive’ campaigns with the oral virus.

eritrea-polio-immu.jpgTiming is crucial for any eradication effort, since a disease can get an upper hand again if efforts stall. An example of the aggressive and timely response is a donation by Rotary International of $500,000.00 immediately to UNICEF & WHO in equal parts to contain the current outbreak in DRC and take preventive measures.

The economic benefits of achieving eradication are spelled out in an article in the current issue of Vaccine. The study estimates net benefits of at least US$40-50 billion if transmission of wild polioviruses is interrupted within the next five years and $17-90 billion in benefits from add-on campaigns such as the life saving effects of delivering vitamin A supplements. Awareness of these benefits should add further impetus to wrapping up of the polio eradication program.

Annually, we are now numbering polio cases in the hundreds and guinea worm cases in the dozens, while still malaria numbers in the millions. We are only at the beginning of the road to an effective malaria vaccine. While researchers and program managers worry about whether vaccine efficacy will be proven in ongoing phase 3 clinical trials in sub-Saharan Africa, Rebecca Voelker has pointed out an equally serious problem, developing and implementing an effective malaria vaccine delivery system.

Regulatory approval is just the first step, according to Voelker.  A functional procurement and supply management (PSM) system is needed to ensure that the malaria vaccines get to the point of delivery. Plans are needed to ensure social acceptability and timely uptake.

Malaria programs have an advantage over polio in that there are several different technologies available from which appropriate package of national and local interventions can be planned. Still, we face PSM challenges with the nets and medicines. Hopefully effective malaria vaccines will come along soon, and that as delivery systems are strengthened for nets and medicines, these too, can smooth the way for introduction of the malaria vaccines.

… and of course, we should learn lessons from the global polio vaccination effort, such as the fact that the last stages of an eradication campaign require constant vigilance.

Vaccine without pain – a future for malaria control

During a discussion organized the Bill and Melinda Gates Foundation, Chris Wilson explained that vaccines are one of most efficient and effective interventions ever developed. Among the discussants was Tycho Speaker who is doing research on transdermal delivery systems using microneedle systems.

Dr Speaker is the primary contributor in developing TransDerm’s proprietary soluble microneedle technology, which is finding utility in skin therapeutics and skin-based vaccinations. This vaccine research has received specific funding for malaria prevention from the Bill and Melinda Gates Foundation under their Grand Challenges Explorations program.

phase-iii-rtss-trials-dave-poland-path-malaria-vaccine.jpgChris Wilson emphasized that, “We need to do better job to ensure vaccines reach people who need them and increase coverage.” The microneedle patch technology may be able to achieve this for malaria vaccines that are in the pipeline.

Normally such technology may take ten years from conceptualization to actual use in the population. Gates has given Dr Speaker’s group a preliminary one year grant to test the concept, and then there is the possibility for a second grant to develop the practical applications of the microneedle patch if the results are encouraging.

The patch actually resembles a bandaid. The microneedles penetrate the skin and dissolve so there is no medical sharps waste. The vaccine itself in made into a powdered form and is stable without the need for coldchain.  The speakers stressed the practicality – the patch vaccines could even be transported on motorcycle to peripheral health facilities that have no electricity.

The patches can be printed with a picture or pattern that appeals to children and parents to address the perennial vaccine problem of community acceptance.  Within 2-10 minutes the vaccine will be delivered.

The discussants concluded that a small increase in compliance can have enormous effect on the vaccination effort overall, especially when there is no pain. It’s good to know that researchers are not simply looking for an effective malaria vaccine, but also for delivery mechanisms that will make the vaccines more acceptable and actually used.

Introducing the International Vaccine Access Center

ivac_logo_wtaglinefinal_resized.jpgBefore reaching her second birthday, an American child will be vaccinated against 14 diseases. A child in sub-Saharan Africa? About 6. Yet the African child will be especially vulnerable to disease due to high rates of malnutrition, co-morbidities, and weak health systems.

What’s more, the American child will have access to new vaccines as they become available. After a 15 to 20 year lag, those same vaccines will finally reach sub-Saharan Africa, perhaps in time for the next generation.

The International Vaccine Access Center, which launches on December 7, seeks to change this scenario by accelerating global access to life-saving vaccines. Vaccine uptake is delayed by a combination of incomplete epidemiological information, outdated policies, and market barriers. For instance, without information on country-specific disease burdens, policymakers are left weighing the upfront costs of revising their immunization program against uncertain future benefits.

As national policies remain unchanged, the potential market looks smaller and smaller to manufacturers. Without confirmed orders, manufactures cannot offer the reduced pricing that makes these products affordable to developing countries.

In the meantime, years pass and kids succumb to diseases that could have been prevented. The 2009 State of the World’s Vaccines and Immunizations Report estimates that existing vaccines could avert the deaths of up to 2 million children if given access to these vaccines.

IVAC sees an opportunity to save lives by shortening the lead-time between vaccine development and vaccine introduction in the developing world. Building on lessons learned from the successful Hib Initiative and Pneumococcal Vaccine Accelerated Development and Introduction Plan (PneumoADIP), IVAC will generate the epidemiological information policymakers need to make informed decisions. “For too long, access to life-saving vaccines has been delayed by the lack of evidence-based policies to support their use and delivery.

The cost of these delays is measureable in lives lost, and IVAC will aim to turn that situation around by using evidence to assure equitable vaccine access globally,” said Orin Levine, Executive Director of the new center.

ivacmodel2.jpgBased at the Johns Hopkins School of Public Health, IVAC will strive to maximize the impact of immunizations, one of the most powerful and cost-effective tools we have for improving child health. Hopefully, success will build upon success, demonstrating to manufacturers the viability of new products in developing markets and generating new investments in child health. While IVAC does not have an official malaria project as of yet, the center is exploring opportunities to accelerate the introduction of a future vaccine.
To learn more about IVAC and childhood vaccination, visit Dr. Levine’s blog at the Huffington Post.

Thanks to Jenna Rose for providing the above information.

Malaria vaccine enters phase 3 clinical trials

A new malaria control tool is closer to joining the arsenal of malaria interventions according to vaccine researchers and their sponsors at a press briefing today during the MIM 5th Pan-African Malaria Conference in Nairobi.

A joint venture between PATH’s Malaria Vaccine Initiative and GlaxoSmithKline Biologicals, with support from The Bill and Melinda Gates Foundation, WHO and African Governments and the participation of African malaria researchers at 11 sites in seven countries has recently completed a successful Phase 2 Clinical Trial of the RTS,S vaccine.

vaccine-and-malaria-life-cycle-sm.jpgMozambique, one of the Phase 2 trial sites reported that, “vaccine efficacy against new infections was 65 percent over a three-month follow-up period after the infants received all three doses of the vaccine. The results also showed that the vaccine reduced episodes of clinical malaria by 35 percent over a six-month follow-up period starting after the first dose.” At the Ghanaian study site it was confirmed that “Three dose schedules were more immunogenic than 2 dose schedules.”

Joe Cohen of GSK Biologicals explained at the press conference that vaccine efficacy in children 5-17 months was 53% after 8 months. The trials also showed that the new vaccine can be integrated into the EPI vaccine process.  Continuing research will determine if it will also be effective in younger children.
Phase 3 trials have started and have already enrolled 5,000 of the expected 16,000 volunteer participants. Reporters were anxious to know when the vaccines might actually be available for general use. The panelists outlined steps that included filing results of Phase 3 and previous trials with regulatory agencies around 2012. If approved, vaccines could be available around 2015. In the meantime partners are gearing up to find funding to support adequate production.

Christian Loureq of the PATH Malaria Vaccine Initiative said that partners ranging from researchers, producers and funders were all thinking ahead.  No one wants the vaccine to sit on the shelf after proving its efficacy.  A decision making framekwork is helping planners identify the data and resources needed to start rolling our vaccines on the day they are approved.

As noted, the partners recognize that an effective vaccine will be only one of the needed interventions to sustain malaria control, especially since the efficacy, though good, is not perfect. Thus, they are already thinking about research for the next generation of vaccines for 2020 or 2025

A key component to planning roll-out is research for understanding the community perspective, recognizing that the mothers who brought their children to the trials are also central partners in this initiative. The EPI program itself is full of lessons about acceptance and dropping out. The 3-dose vaccine regimen will certainly pose many implementation challenges, but hopefully the malaria community will be ready to tackle these.