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Full Q&A Webinar Transcript: The Malaria Vaccine, A Bold Frontier. A conversation with PATH’s Malaria Vaccine Initiative

by | Jul 12, 2021

  1. Can you compare and contrast the R21 malaria vaccine candidate tested in Burkina Faso with the RTS,S vaccine in pilot implementation in Ghana, Kenya, and Malawi?

Answer: The short answer is that the efficacy of RTS,S/AS01 and R21/Matrix-M may be very similar, although it’s not possible to say definitively given the way the two vaccines were administered at this particular site, among other factors.

  • The Phase 3 trial of RTS,S was conducted at 11 sites in 7 countries, one of them being the same Nanoro site in Burkina Faso where R21 was evaluated.
  • The Phase 2 trial of R21 was conducted at just this one site in Burkina Faso.
  • Analysis by PATH, WHO, and other experts tends to see the site-specific data on RTS,S, over 6 months of follow-up, as broadly comparable to the R21 data reported. The vaccine efficacy of 72% reported for RTS,S in Nanoro is not statistically different from the 77% reported for R21.
  • It is important to remember that R21 and RTS,S are in different places along the development pathway. R21 is just starting a Phase 3 trial, having been evaluated in a few hundred people. RTS,S has successfully completed Phase 3 trials in which more than 10,000 children received the vaccine. RTS,S was also positively reviewed by a so-called “stringent” regulatory agency (the European Medicines Agency) before being recommended by WHO for large scale pilot implementation.
  • We look forward to having more data on R21, including data on its safety and efficacy in a range of different malaria transmission settings, which we hope will come from Phase 3 trials. If these data are positive, we would welcome having multiple malaria vaccines in the market.

 

  1. Can you explain a little more about where RTS,S fits into efforts to control and eventually eliminate malaria?

Answer: One thing we may want to keep in mind is that malaria control, elimination, and eradication exist along a continuum. One first has to control a disease before one can eliminate it from a particular geographic area, and from there move to eradication, which would mean the absence of circulating malaria parasites globally. (Ashley): It is important to note that this is a vaccine targeting prevention of disease and death; it is not currently regarded as being a tool to help eliminate or eventually eradiate malaria. However, this goal of reducing disease and death is very important, given the stalling of progress against malaria in recent years. We still have a long way to go to eliminate malaria from some countries; controlling/reducing the disease is a critical first step.

  • RTS,S is a first-generation vaccine to reduce disease and death due to malaria among young children, rather than to eliminate malaria.
  • It is also a complementary tool, designed to be used alongside other proven malaria interventions.
  • RTS,S will have the greatest impact in settings of moderate to high malaria transmission—in other words, in places where malaria elimination is unlikely to happen for a number of years.

 

  1. We hear a lot about herd immunity in connection with driving down or even eliminating Covid-19. Is this concept relevant to malaria vaccines? To RTS,S?

Answer: In the case of a vaccine like RTS,S, the concept of herd immunity doesn’t really apply, because it is currently intended for use only in young children—i.e., a relatively small proportion of the total population—to help protect them against disease and death.

  • Herd immunity could come into play if we had a malaria vaccine that is highly efficient at preventing infection and/or transmission AND is deployed across an entire population, rather than a particular age group.
  • We are a long way from having such a vaccine, but it remains an important long-term goal.

 

  1. The RTS,S malaria vaccine is an exciting development. Especially for children. Will adults be vaccinated also?

Answer: Currently, the RTS,S malaria vaccine is only intended for use in young children.

  • While it has been tested in other age groups (it was first tested in adults, of course), the greatest public health impact for RTS,S continues to align with deployment among young African children living in areas of moderate to high transmission. Hence, this demographic remains a primary focus.
  • While it has been tested in other age groups (it was first tested in adults, of course), there are not enough data to support its use in other age groups, as yet.

 

  1. Who will have access to vaccines and how will that be determined?

Answer: Currently, the RTS,S malaria vaccine is only intended for use in young children.

  • With a WHO recommendation on broader use possible later this year, a process for allocating the available supply of RTS,S will need to be determined and involve key stakeholders—especially African countries themselves.
  • How the vaccine will be rolled out, in terms of country introductions, is currently under discussion. Many factors will need be considered and difficult decisions will need to be made, particularly if there are periods where demand exceeds supply, which is common for new vaccine introductions. It is our hope that if recommended for broader use, all countries that want to deploy the vaccine are able to access it.

6. Will this be implemented in only certain countries, as in the pilots, or across Africa more generally?

Answer: Right now, we are waiting to see if WHO advisory bodies on malaria and immunization view the data generated by the pilot program and other evidence as sufficiently positive to warrant a recommendation for broader use. If recommended for broader use, we would expect WHO to provide guidance on the settings in which the vaccine should be used.

7. Rotarians had a very large role in eradicating polio in Africa. Where do you think Rotarians might have a role when it comes to malaria vaccines How can Rotarians best support vaccination efforts when time comes?

Answer: There are several ways that Rotarians might be able to help, both in the short and the longer term.

  • First, Rotarians can speak out about vaccines in general. Vaccine hesitancy may not be a big problem in most of Africa, but inaccurate information does circulate.
  • Second, if the WHO recommends broader rollout of the RTS,S malaria vaccine, Rotarians can encourage their governments to make informed, evidence-based decisions regarding whether or not to adopt it in their country.
  • Third, there may be ways for Rotarians to support the costs of deployment, for example, by investing in people. This might mean supporting the training of health care workers or pharmacists.

8. How is the public sensitized to the vaccine? Are there media campaigns to address vaccine hesitancy or misinformation?

Answer: Communications is a key part of any vaccine introduction. This includes preparation of training material for health care workers; posters, radio jingles, community meetings, and other approaches for reaching care givers directly; and working with reporters to ensure that they have accurate information about the vaccine. Important to keep in mind is that this kind of communications effort needs to be an ongoing process, not a one-time activity.

9. How accessible will be the vaccine in terms of cost and availability?

Answer: The price of the vaccine has yet to be determined, as that will depend on the demand for the vaccine, which in turn depends on it being recommended for broader rollout, as well as country decisions regarding adoption.

  • This said, GSK has for many years stated its commitment that the price will be the cost of goods plus a return of no more than 5%. They do not intend to recoup the costs of developing the vaccine.
  • Also, GSK has already committed to supply up to 15 million doses annually of the vaccine, even before the vaccine is recommended for use or financed. However, projected potential demand is expected to rapidly exceed this supply commitment and investment will be needed to ensure timely resolution of this anticipated supply-demand imbalance.

10. Other factors in eradicating malaria involve vector control, rapid diagnosis and treatment, improved surveillance for better data, as well as effective use of data, and stronger health systems overall. How is PATH involved in these areas?

Answer: PATH’s work to control and eliminate malaria includes evaluation of new vector control tools, development and testing of diagnostic tests, vaccine development and introduction, the use of data to inform malaria programming, and more.

    • Our work in malaria encompasses 22 African countries and another 12 countries in Asia and Latin America.
    • In all our work, we collaborate with others, including Malaria Partners International.
    • In Zambia, for example, our efforts include capacity building for health facilities and community health workers, to improve malaria surveillance data for decision-making, and to increase the uptake and impact of malaria control measures in selected districts.
    • Specifically with Malaria Partners International and Partners for a Malaria-Free Zambia, we are helping to training up to 2,500 community health workers—key to stronger health systems overall.

11. Since we have now seen how rapidly an effective mRNA vaccine can be developed to Covid-19, what is the status of mRNA vaccines for malaria? Are any under development now, and is PATH facilitating or supporting any? 

Answer: Firstly, it is important to keep in mind the very different pathogens involved in COVID-19 and malaria, COVID-19 being caused by a less complex virus involving just a few dozen genes and malaria being cause by a parasite with more than 5,000 genes. The implications of this are that there is little scientific debate on the best regions of the virus to target with vaccines; this is not the case for malaria. Secondly, the magnitude of sustained immune response needed to protect against malaria using current targets is much higher than for COVID-19 (and any other infectious disease) and therefore more difficult to maintain; hence protective immunity tends to wane relatively rapidly for malaria. Nonetheless, we do feel it is important to assess the potential of mRNA vaccines for malaria and PATH is actively engaging in these efforts. Currently, work is at a relatively early stage (i.e., mouse studies), but we hope to see progression to initial clinical trials over the next few years.

12. African economies would seem to be negatively affected by the morbidity as well as the mortality of malaria. Are there statistical models of the impact of eradicating malaria on the economies of sub-Saharan African countries? Would those suggest a strong economic rationale for investing in malaria eradication via vaccination?

Answer: While no one argues against eradicating malaria, the economic returns for eradication have not been reliably estimated; easier to model is the benefit of eliminating malaria from a country or group of countries. A recent analysis by the World Health Organization concluded malaria elimination would tend to have the greatest benefit for low-income countries with the highest incidence of malaria; in this group of countries, eliminating malaria would be associated with an increase in per capita income of nearly 20%. That would be significant. (See Report of the WHO Strategic Advisory Group on Malaria Eradication, 2020, pp. 9-10).

  • Malaria vaccines like RTS,S are intended to bring down the burden of disease among young children, so would not be a tool for eradicating malaria.
  • As noted before, malaria control, elimination, and eradication exist along a continuum. One first has to control a disease before one can eliminate it from a particular geographic area, and from there move to eradication, which would mean the absence of circulating malaria parasites globally.
  • Eradication of any disease is a tall order – we’ve only done it once, with smallpox, although we are getting closer to eradicating polio. Eradicating malaria has additional complexities, including the high incidence of asymptomatic carriage (infected people often have no visible signs of infection) and the role of an intermediate mosquito vector; however, it is the only acceptable long-term goal.

13. With HIV and TB, malaria has been targeted for increased attention from health advocates from the developed world for the benefit of the developing world, particularly Africa. Are these three diseases viewed similarly in Africa, and what lessons might we learn from the perceived differences between them?

Answer (John): While PATH works on all three diseases, I have worked mostly on malaria. With respect to malaria, I can say that the pilot implementation of the RTS,S malaria vaccine is showing that people are very aware of the impact of malaria on their families, especially their young children, and they perceive the vaccine as making a positive difference. Of course, we will have to see what the data say, but this is what people are saying. Growing up in Ghana, malaria was a fact of life, but also of death. People are tired of their children dying of malaria. It is no longer acceptable.

14. How will the news coming out of Burkina Faso about the efficacy of a new malaria vaccine change the fight to end malaria?

Answer: Based upon analysis by PATH, WHO, and other experts, it is likely that the efficacy of R21/Matrix-M—the vaccine candidate that reported Phase 2 trial results from Burkina Faso in April 2021—and RTS,S/AS01 may be very similar, although it’s not possible to say definitively given the way the two vaccines were administered at the particular site in Burkina Faso. If this expert analysis ends up being validated by data from larger Phase 3 studies of R21, conducted in different transmission settings, we could anticipate having multiple malaria vaccines in the market at some point—a welcome development, given that the projected potential demand for a malaria vaccine is expected to rapidly exceed projected vaccine supply in the near- to medium-term.

  • It is important to keep in mind that R21 and RTS,S are at different points along the development pathway. R21 is just starting a Phase 3 trial, having been evaluated in a few hundred people. RTS,S has successfully completed Phase 3 trials in which more than 10,000 children received the vaccine. RTS,S was also positively reviewed by a so-called “stringent” regulatory agency (the European Medicines Agency) before being recommended by WHO for large scale pilot implementation.

15. How long the vaccine expected to rollout in India and how can NGOs activist like us to be associate with the process and support the malaria affected community.

Answer: The RTS,S malaria vaccine was designed and developed for use in sub-Saharan Africa and is currently manufactured by GSK. While an agreement to transfer the product, including manufacture of the RTS,S antigen, to Bharat Biotech, was announced in January of this year, it could take until as late as 2029 for Bharat to begin supplying the vaccine. Any use of the vaccine in India would need to be discussed by Bharat with Indian regulators and any regulatory requirements fulfilled. However, it is important to note that unlike in Africa where P .falciparum is the dominant parasite, the dominant parasite in India is P. vivax and targeting this parasite would require an additional vaccine component.

16. Why the emphasis on meningitis?

Answer: Meningitis was mentioned during the webinar in the context of the Phase 3 trial results, which showed an imbalance in the number of meningitis cases between children receiving and not receiving the RTS,S vaccine. This was regarded by the EMA as possibly being a chance finding and was flagged for follow-up in any subsequent vaccine safety monitoring. Data from other studies of the vaccine, as well as from the large pilot implementation, have been described as reassuring—i.e., that meningitis does not appear to be causally related to the vaccine.

17. What is it about immune system response to the malaria parasite in adults that mitigates the severity of the disease?

Answer: Repeated exposure to malaria parasites among adults living in areas with considerable malaria transmission results in a kind of natural immunity that affords some protection against illness. A person may still be infected with parasites by a mosquito (and thus be infectious) but does not necessarily become ill.

18. Four injections seems like a challenging treatment. What constraints does that impose on where/how the vaccine can be administered?

Answer: Community demand for the 4-dose vaccine has been good during the pilot program and has steadily increased since the pilot introduction launch in 2019, even in the context of COVID-19. Administrative reports indicate high coverage levels for dose 1 achieved in 2020 that increased further in 2021 (February–April), to 91% in Malawi and Kenya, and 72% in Ghana, with some drop off for subsequent doses, the latter improving over time.

  • Each of the three countries in the pilot program—Ghana, Kenya, and Malawi—looked at existing child health visits and their uses (i.e., for giving Vitamin A, other vaccines, growth monitoring, and the like). Each country then decided on a vaccine schedule they thought would work best for them—in the context of a growing effort to ensure that children receive health care into the second year of life and beyond.

19. If 2 million vaccine doses have been administered, why is it that only 700,000 children have received at least one dose? Could you explain this large difference?

Answer: In the pilot introduction children will ideally receive 4 doses of the vaccine during the first 2 years of life. Each of the 700,000 children vaccinated thus far has received one or more vaccine doses, depending on when they had their first dose.

  • The first three doses of RTS,S are given about one or two months apart, starting at 5 or 6 months of age (as decided by each country), followed by a fourth dose given at about 2 years of age.
  • The fourth vaccine doses began to be administered last fall (i.e., September 2020).

20. What is the estimated “cost” of the vaccine – and are their specific logistical (cold chain) challenges.

Answer: The price of the RTS,S vaccine has yet to be determined, as that will depend on the demand for the vaccine, which in turn depends on it being recommended for broader rollout, as well as country decisions regarding adoption. There are no specific cold chain challenges associated with the vaccine; it is stored at a similar temperature to many other vaccines, i.e., at between 2° and 8° Celsius.

21. Interesting slide comparing funds for COVID and malaria vaccines. Does the R&D funding pie chart cover all malaria vaccines or only RTS,S vaccine?

Answer: The R&D funding pie chart for malaria shows average annual spending of $673 million for all R&D investments to combat the disease—i.e., drugs, diagnostics, vaccines, vector control tools, as well as basic research. This average is based upon three years of data (2014–2016), and is in contrast to the $5.5 billion spent on COVID-19 vaccine R&D as of March 2021.

22. I am a Rotarian organising projects in Uganda. When will the vaccine be available in Uganda?

Answer: It’s not possible to answer this question at this time, as RTS,S has not yet been recommended for broader use by WHO, which needs to happen before Gavi makes a financing decision and before countries make their own decisions regarding whether or not to adopt the vaccine.

23. Regarding integration – how well are the pilots doing at linking with other childhood interventions late in first year and during second year of life? And… do you have a date for WHO SAGE discussion of expansion sites?

Answer: The design of the pilots was carefully considered to leverage other healthcare visits, to achieve synergy between childhood interventions where possible and to support the provision of routine healthcare in the second year of life. For example, all three countries administer Vitamin A at 6 months of age and seek to use this same healthcare visit to give either the first or second dose of the RTS,S vaccine. A second dose of Vitamin A is given at 24 months; this coincides with the administration of the fourth RTS,S dose in Ghana and Kenya (Malawi’s schedule for RTS,S vaccinations is slightly different). Currently, WHO advisory bodies on malaria and immunization (MPAG and SAGE) are expected to review the available evidence and consider possible broader use of the vaccine at a meeting scheduled for October of 2021. If positive, this recommendation would be for routine rollout, rather than an expansion of the pilots (the pilots are scheduled to conclude at end-2023).

24. Is there any planning to combine seasonal malaria chemoprevention (SMC) and RTS, S vaccination?

Answer: The London School of Hygiene and Tropical Medicine is currently evaluating the RTS,S/AS01 malaria vaccine compared to and in combination with seasonal malaria chemoprevention (SMC), as a possible tool to more effectively combat malaria in young children. Approximately 6,000 children are participating in this Phase 3 study, which is being conducted in Mali and Burkina Faso. Results from the first three years of the five-year study have been submitted for publication in a peer-reviewed journal. Once those data are publicly available, it would be up to WHO advisory bodies and countries to consider the implications of those study results for possible use of the vaccine in highly seasonal settings.

25. Can you please address coverage of the 4th dose and how that impacts protective efficacy?

Answer: It is still too early to assess coverage of the fourth dose of RTS,S, in the pilots as the first children to receive the vaccine (in April 2019) only began receiving the fourth dose last fall (September of 2020). As explained below, data show that children who receive 3 vaccine doses are not at increased risk of severe malaria through rebound, and there is a benefit from 3 or 4 vaccine doses. Mathematical models predict that, over 10–15-years of follow-up, more than 90% of vaccine impact is realized through the administration of the first 3 vaccine doses. Understanding the added value of the fourth dose is one reason why it is important to continue the pilots for the full evaluation of period (i.e., until 2023); this question will also be addressed in case-control studies that were recommended by the independent advisory group for the pilots.

  • Data from the large Phase 3 efficacy and safety trial conducted at 11 research centers in 7 African countries between 2009 and 2014 indicated that 4 doses were needed to sustain efficacy over 4 years of follow-up. After the conclusion of that study, 3 of the 11 research centers conducting the Phase 3 trial continued follow-up for an additional 3 years, bringing the total period of follow-up to 7 years.
  • This longer period of follow-up and a reanalysis of some data from the original Phase 3 trial show that children who receive 3 vaccine doses are not at increased risk of severe malaria through rebound, and there is a benefit from 3 or 4 vaccine doses. This is one reason why WHO advisory bodies have agreed that a WHO recommendation regarding possible broader use of the vaccine may not require high vaccine coverage (including with the fourth dose). Mathematical models also indicate that over 10-15 years, more than 90% of vaccine impact is realized through the administration of the first 3 vaccine doses, with small incremental benefit of the fourth dose.
  • The independent advisory group for the pilot program recommended case-control studies to gather additional evidence on the incremental value of the fourth dose, as well as other data.

26. How safe is the Malaria vaccine and will this cover youth?

Answer: In large-scale clinical testing involving thousands of African children, the RTS,S vaccine was generally well tolerated, with adverse reactions similar to those of other childhood vaccines. In 2015, the European Medicines Agency issued a positive scientific opinion of RTS,S indicating that the benefits of the vaccine in preventing malaria outweigh potential risks. The national regulatory authorities in each of the pilot countries—Ghana, Kenya and Malawi—have reviewed and authorized the RTS,S vaccine for use in phased introductions in their countries.

Safety of the RTS,S vaccine is a top priority and is currently being monitored in three ways: first, through the evaluation components of the pilot program that are overseen by WHO; second, through Phase 4 studies being conducted by GSK; and third, through case-control studies moving forward under the leadership of the Kintampo Health Research Centre in Ghana.

27. Are you experiencing resistance to vaccination? Will you be initiating a media/poster campaign? Will PATH be supporting contributing factor, such as training of community health workers?

Answer: Community demand for the vaccine has been good and has steadily increased since the pilot introduction launch in 2019, even in the presence of COVID-19. While there are efforts to discredit vaccines every time a new one is introduced, we have seen the ministries of health respond very effectively to misinformation. Indeed, we have seen a kind of evolution of opinion over time, from a general level of trust in the immunization program to a more RTS,S-specific confidence. In Ghana, where I live and work, a recent nationwide survey (the Malaria Indicator Survey) showed very high levels of awareness about the vaccine pilots and, more importantly, that most caregivers indicated they would bring their child to be vaccinated with RTS,S, if the vaccine was widely available.

Communications is a key part of any vaccine introduction. This includes preparation of training material for health care workers; posters, radio jingles, community meetings, and other approaches for reaching care givers directly; and working with reporters to ensure that they have accurate information about the vaccine. Training of community health care workers is critical to the success of immunization programs, and we have worked with health ministries to help support ongoing training of health care workers.

28. If we spent 5 billion on malaria vaccine where would we be?

Answer: I answered this question briefly during the webinar and suggested that we should split this kind of investment between R&D for next-generation vaccines, and on making available the vaccines we have, assuming the evidence supports their deployment. We need to speed up the scale-up to meet the potential demand for malaria vaccines and to fill any gaps in evidence to support their optimal use.

29. Can you develop resistance and mutations from these vaccines?

Answer: Vaccines do not cause mutations and people do not develop resistance to vaccines. It is important to keep in mind that the greatest risk factor in mutation of a pathogen comes from it being in circulation: the more pathogens in circulation, the more opportunities for some of them to evolve in ways that make a treatment or preventive medicine less effective—think about what we have seen with COVID-19 and the emergence of the Delta variant, due primarily to the fact of ongoing transmission of the coronavirus and too little vaccination, rather than too much.

The RTS,S vaccine primarily targets a highly conserved region of the parasite and has shown generally consistent efficacy across multiple settings in sub-Saharan Africa. Nonetheless, the genetic profile of circulating strains has been monitored during the course of clinical trials and it will be important to maintain these efforts in the event the vaccine is deployed broadly to ensure we remain well informed on the evolving relationship between vaccine induced immunity and circulating parasite strains.

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