GlaxoSmithKline Malaria Vaccine Candidate Results Disappointing

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The latest clinical trial of the world’s leading malaria vaccine candidate produced disappointing results on Friday. The infants it was given to had only about a third fewer infections than a control group. Three shots of the vaccine, known as RTS, S or Mosquirix and produced by GlaxoSmithKline, gave babies fewer than 12 weeks old 31 percent protection against detectable malaria and 37 percent protection against severe malaria, according to an announcement by the company at a vaccines conference in Cape Town.

Read more, via The New York Times.

Malaria Vaccine

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QUESTION

What is the shot you get to prevent malaria?

ANSWER

There is currently no shot available to prevent malaria. The most promising vaccine candidate, called RTS,S and being developed by GlaxoSmithKline, is currently undergoing Phase III trials in children in Africa.

Preliminary results have indicated it may prevent up to 50% of malaria cases, though this varies by age group and long term data are not yet available. The full results of the study will be published in 2014.

Why not create a vaccine for malaria?

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QUESTION

Why not create a vaccine for malaria?

ANSWER

There are many teams of scientists working hard to try to produce a malaria vaccine. In fact, only last year, the preliminary results of a vaccine trial were published. The vaccine, called RTS,S, has been produced by GlaxoSmithKline and is in the midst of Phase III trials in Africa.

The preliminary results showed approximately a 50% reduction in malaria incidence, though it is not clear how much of that protection came from the vaccine and how much should be attributed to the vaccine adjunct (a compound given with the vaccine to boost immune responses). The preliminary results also did not include analysis of how much the vaccine prevented mortality due to malaria, and levels of protection against severe malaria appeared to be low.

However, we will have to wait until 2014 for the full and final results of the clinical trial to be made available. In the meantime, other vaccine candidates are being developed, but there are many challenges to overcome. For example, there are five different types of malaria that infect people: these differ significantly in the way they develop in the human host, and so a vaccine appropriate for one may not be effective against the others.

Most vaccine researchers are focusing on Plasmodium falciparum, the most deadly form of malaria, and a vaccine effective against this parasite would certainly do the most to reduce malaria-related mortality. However, Plasmodium vivax also causes high morbidity, particularly in Asia and the Pacific, and so should not be overlooked. Moreover, within each of these species exist different strains in different areas, each of which can be markedly different from a genetic perspective.

Finally, we do not yet fully understand the complex ways in which our immune system reacts to malaria. As such, this presents a challenge to developing an effective malaria vaccine, though many scientists are willing to address this challenge and have made big inroads in the search for a safe, effective vaccine.

Another stumbling block has been inadequate financial commitment; increased resources devoted towards vaccine development would help overcome the scientific and technical obstacles in our way. PATH, coordinating the Malaria Vaccine Initiative, mentions for example that it can cost up to half a billion dollars ($500,000,000!) to fund a vaccine through the full process of development, testing and clinical trials through to licensing.

Malaria Vaccine Research

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QUESTION

Is there any research to produce anti malaria vaccine, if not, why?

ANSWER

There are many teams of scientists working hard to try to produce a malaria vaccine. In fact, only last year, the preliminary results of a vaccine trial were published. The vaccine, called RTS,S, has been produced by GlaxoSmithKline and is in the midst of Phase III trials in Africa. The preliminary results showed approximately a 50% reduction in malaria incidence, though it is not clear how much of that protection came from the vaccine and how much should be attributed to the vaccine adjunct (a compound given with the vaccine to boost immune responses).

The preliminary results also did not include analysis of how much the vaccine prevented mortality due to malaria, and levels of protection against severe malaria appeared to be low. However, we will have to wait until 2014 for the full and final results of the clinical trial to be made available. In the meantime, other vaccine candidates are being developed, but there are many challenges to overcome.

For example, there are five different types of malaria that infect people: these differ significantly in the way they develop in the human host, and so a vaccine appropriate for one may not be effective against the others. Most vaccine researchers are focusing on Plasmodium falciparum, the most deadly form of malaria, and a vaccine effective against this parasite would certainly do the most to reduce malaria-related mortality. However, Plasmodium vivax also causes high morbidity, particularly in Asia and the Pacific, and so should not be overlooked.

Moreover, within each of these species exist different strains in different areas, each of which can be markedly different from a genetic perspective. Finally, we do not yet fully understand the complex ways in which our immune system reacts to malaria. As such, this presents a challenge to developing an effective malaria vaccine, though many scientists are willing to address this challenge and have made big inroads in the search for a safe, effective vaccine. For more information on current efforts to develop a malaria vaccine, please see PATH’s Malaria Vaccine Initiative.

Malaria Vaccine

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QUESTION

For how long does this vaccine work?

ANSWER

There is not yet a commercially available vaccine against malaria. Recently, results were published (in the New England Journal of Medicine – press releases and news reports about the study are available through the main page of www.malaria.com) presenting preliminary findings of the first Phase 3 clinical trial for a vaccine, called RTS,S. The trial will not fully conclude until 2014, and so we won’t know for a few more years exactly how effective it is or for how long. The results that were just published showed only a 50% level of protection against malaria from the vaccine (in African children, most of whom also slept under bednets and generally had access to a high standard of medical care), and that value appeared to decrease over time, with protection levels after a year only about 35%. However, these early findings are still potentially promising, especially for remote areas with low access to other more immediate health care options.

The “E” word and the “V” word: Two Holy Grails of Malaria Control

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The Roll Back Malaria Partnership talks confidently of elimination—many others question if this is possible without new interventions. The recent publication of the first Phase 3 clinical trial for a malaria vaccine shows promise, but is it actually good enough?

REVIEW OF:

  • Roll Back Malaria Partnership, “Eliminating Malaria: Learning from the Past, Looking Ahead”, Progress & Impact Series, vol 8, October 17th, 2011
  • RTS,S Clinical Trials Partnership, “First Results of Phase 3 Trial of RTS,S/AS01 Malaria Vaccine in African Children”, New England Journal of Medicine, October 18th, 2011

This past week has been a busy one in the world of malaria research and control. On Monday, the Roll Back Malaria Partnership (a joint enterprise between the World Health Organisation, UNICEF, UNDP and the World Bank) released the 8th volume in its Progress & Impact Series, entitled, “Eliminating Malaria: Learning from the Past, Looking Ahead”. The report summarizes RBM’s malaria eradication and elimination efforts to date, and outlines action plans and on-going progress in all malaria-endemic countries around the world. The overall tone of the document is highly positive, emphasizing the various success stories of countries achieving or nearing elimination of malaria in different parts of the world.

This is nowhere more obvious than in Chapter V’s regional summary of the WHO African Region, where no mention is made of the countries that are struggling the most with malaria control, but instead the focus is entirely on congratulating the 4 countries that have already achieved elimination, and praising those 12 countries with existing or imminent plans to move towards elimination. The document as a whole is a comprehensive overview of the status of malaria control, although somewhat light on epidemiological specifics. I was also dismayed to see at least two large photographs of fingerprick blood samples being taken without protective gloves being worn, against all standard diagnostic protocol!

But that’s an aside. In their conclusion, the authors primarily support “existing interventions”, and caution against waiting for “better options” to become available, given the measurable successes already being achieved in many settings using already-available control strategies such as bednet distribution, improved access to diagnosis and treatment and vector control.

It is not perhaps without a touch of irony then that on Tuesday, the first comprehensive analysis of an on-going Phase 3 clinical trial for one of the most promising malaria vaccine candidates was published, in the New England Journal of Medicine. The quest for a malaria vaccine has been protracted, expensive and, thus far, basically unsuccessful, yet to many, global elimination of malaria will not succeed without an intervention that gives lasting protection against re-infection, given the extraordinarily high rates of transmission of malaria in some parts of the world.

The paper reports a reduction of clinical malaria and severe malaria by 56% and 47% respectively, although protection seemed to decay over time; further evaluations will be analysed in 2012 and at the conclusion of the trial in 2014. The authors of the paper are careful to note that the trial was conducted in a cohort with generally good access to medical care, well-supplied health facilities and widespread usage of bednets and other control interventions. As such, mortality from malaria was low even in the control group, and so conclusions about the impact of the vaccine on malaria-related deaths may be difficult to draw.

Moreover, the paper did not directly analyse the relationship between the antibody titers (levels of immune protection to malaria in the blood) conferred by the vaccine and if the patient got malaria or not. In previous studies (for example, Bejon et al.’s 2008 paper also in the NEJM), this relationship was weak, suggesting that the vaccine itself was not contributing strongly to levels of protection against infection, and that other factors were at play. One suggestion is that the adjuvant, a non-specific immune-response enhancer included in the vaccine, may itself play a role, and given that the control groups received vaccines with a different adjuvant, this may partially account for the variations in malaria prevalence seen between the children studied. However, these early data still show potential at least for reducing clinical cases of malaria in a highly-endemic African setting.

It should be noted that these findings do not come entirely as a surprise; there were early signs of potential, at least partial, protection from this vaccine (the results of the Phase 2b trials were published in The Lancet back in 2004). Despite this, the word “vaccine” is mentioned but twice in the latest RBM report. I have a deep admiration for the RBM and all that the partnership has achieved thus far in the struggle to control malaria throughout the world. Without a doubt, the scale of the problem is immense, and they are right to emphasise the enormous achievements many countries have realized, and particularly in reducing malaria mortality in the last 10 years. Nor would I advocate for countries to latch onto the promise of a vaccine too quickly; clearly more research is needed to evaluate the long-term efficacy of the vaccine, as well as its impacts specifically on mortality as opposed to morbidity; hopefully we will have some of these answers in a year, at the conclusion of the Phase 3 trial.

However, in the meantime, there is clearly a huge opportunity for using these preliminary findings to determine what role there might be, if any, for the vaccine in its existing form as part of new and improved control strategies. For example, if the vaccine is not fully protective, might it, perhaps counter-intuitively, actually be more effective in areas which are already well on their way to successful control, by reducing transmission below that which is viable for the persistence of malaria? Or will its role in reducing incidence of severe disease be equally well utilized in extremely high prevalence and low health infrastructure areas, where access to diagnosis and treatment is the limiting step in effecting control? To its credit, RBM has acknowledged this since the publication of the vaccine trial results, with the following statement from the CDC: “These promising vaccine trial results add to the hope that adding an effective vaccine to current malaria interventions will move us closer to that goal.” Perhaps the “better option” wasn’t so long in coming after all.

 

GSK and Johnson & Johnson Announce Malaria Vaccine Collaboration

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GlaxoSmithKline Biologicals (GSK Bio) and Crucell NV (Johnson & Johnson) have announced a collaboration to develop a vaccine approach aimed at boosting the efficacy of the world’s most clinically advanced malaria vaccine candidate, RTS,S.

The PATH Malaria Vaccine Initiative (MVI) today congratulated the companies on the partnership. “We are excited by the potential of this new endeavor for the field of malaria vaccine development overall and very pleased with the way in which the effort announced today aligns with MVI’s own research and development strategy,” said Dr. Ashley Birkett, director of pre- and early-clinical research and development at MVI. “The agreement between GSK Bio and Crucell is an example of the kind of collaboration that will be required to achieve the community’s goal of a highly effective, next-generation vaccine.”

MVI has strong and successful collaborations with each of the parties to this new agreement. MVI has worked in collaboration with GSK Bio since 2001 and is currently supporting the Phase 3 trial of RTS,S. Under an agreement with Crucell, MVI will support the first test in humans of a vaccine approach that includes weakened cold viruses coupled to a protein similar to that used in RTS,S (Ad35.CS and Ad26.CS). The newly announced collaboration will focus on a “prime-boost” approach, using the Crucell cold virus-derived vaccine candidate (Ad35.CS) as a first dose (prime), followed by two doses of the GSK vaccine candidate (RTS,S) to enhance the body’s ability to fight the parasite.

“With a first malaria vaccine on the horizon, we need to be thinking about how to prepare for this major breakthrough in the battle against malaria,” said Dr. Christian Loucq, director of MVI. “At the same time, this new agreement highlights the importance of investing in the development of next-generation vaccines—including those that build on the success to date of RTS,S—so that we can continue to close in on the elimination of this deadly disease.”

“MVI is committed to attaining a world free from malaria,” Dr. Loucq concluded. “We applaud this endeavor between two of our industry partners and hope that it will inspire others to join together in pursuit of ever more effective malaria vaccines.”

Source: PATH Malaria Vaccine Initiative (MVI)