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Wayne R. Hogrefe, Ph.D | April 07, 2017

Vaccines in the Fight against Malaria

Learn the new approaches required for Malaria vaccine development and explore how the genetic engineering of mosquitoes could reduce the global burden of this widespread disease
The theme for this year’s World Immunization Week, “#VaccinesWork”, rings true for the many diseases from which vaccines are protecting people of all ages across the globe.  Yet, there are more diseases, for which vaccines may work, once they make it through all the development phases into the hands of the patients who need them.  For example, drug resistance and large populations at-risk contribute to the pressing need for development of a malaria vaccine that works.

Malaria – Still a deadly threat
Malaria has been, and still is, among the world’s deadliest diseases. King Tut and Genghis Khan died from malaria, as may up to half of the people who have ever lived.1 There were 212 million cases of malaria in 2015.2 Malaria mainly affects poor resource nations, with the highest transmission found in southern Africa and in parts of Oceania such as Papua New Guinea. Asia also has high prevalence in Vietnam, Thailand, and India. These are areas with climatic factors that allow for survival and multiplication of the vector responsible for transmission, the female anopheles mosquito.2

Current actions being taken to fight malaria center around 1) prevention including education, 2) fast and reliable diagnostic methodologies, and 3) effective treatment that also addresses resistance. Unfortunately, each of these approaches is met with substantial challenges.  Behavior-based prevention measures can be unreliable when not used correctly and mosquitoes are developing resistance to some insecticides. Diagnostic methodologies are sometimes limited by infrastructure availability, and drug resistance has been observed in three of the five malaria species known to affect humans.3

New approaches: Funding dictates progress
GlaxoSmithKline is the first and only sponsor to reach stage 3 trials for a malaria vaccine4.  Q2 Solutions has been involved in a malarial vaccine study with Sanofi and with the Medicines for Malaria Venture (MMV) previously, but the disease area has seen limited new candidates for vaccines over the last 10 years.  The mixed results and limited efficacy shown in trials to date across multiple sponsors pose a challenge to future investment in Malaria vaccine development.

The majority of funding for malaria vaccine development comes from non-governmental organizations, such as the Bill & Melinda Gates Foundation. Funding also comes from the European & Developing Countries Clinical Trials Partnership (EDCTP), the Malaria Vaccine Initiative with a focus on prevention, and Medicines for Malaria Venture (MMV) with a focus on treatment. 

Vaccines
Because of the complex nature of malaria, the best way to approach vaccine development is not altogether clear. Current efforts focus on three approaches: 
  • transmission-blocking vaccines that inhibit transmission from the mosquito
  • pre-erythrocytic vaccines, and 
  • blood stage vaccines.5
Of the three approaches, pre-erythrocytic vaccines have received the most attention, yet have shown only modest success.  Various methods within pre-erythrocytic vaccine development highlight the complex nature of the task at hand. The only malaria vaccine to demonstrate limited effectiveness and provide protection beyond a short time frame utilized repeated exposure to irradiated sporozoites.  Studies with RTS,S,  a circumsporozoite protein fused to hepatitis B surface antigen, showed modest (30-50%), but short-lived protection.5 Other mixed antigens, prime-boost strategies, novel antigens, and new adjuvants are in phase 1 and 2 studies. Additionally, strategies to enhance CD8+ T cell immunity are needed for pre-erythrocytic vaccines, and multiple vaccination schemes are being tried to enhance the CD8 response.5

Alternative non-vaccine approach: ex: Genetic engineering
New advances in genetic engineering have brought new hope to conquering the disease. Some scientists are experimenting with how they could alter the genetic code of mosquitoes to stop malaria transmission. The four main genetic approaches focus on:
  1. disrupting mosquito fertility, thus reducing multiplication of the malaria host
  2. driving the Y chromosome in mosquitoes to increase the 50/50 chance over X chromosome (resulting in fewer female mosquitoes)
  3. limiting the ability of malaria to replicate within mosquitoes, making the mosquito a poor host, and 
  4. decreasing the number of times the mosquito feeds, thus providing less opportunity to pass malaria on to the human host.

The role of specialty central laboratories

Malaria vaccine development requires specialty lab testing that only a specialty central lab contract research organization (CRO) can provide.  Clinical research on the prevention and treatment of malaria in Sub-Saharan Africa occurs mainly in West, Central and East Africa requiring a laboratory solution that utilizes both local and central laboratories.  

At Q2 Solutions, we have developed testing to support the central laboratory testing needs, including quantitative polymerase chain reaction (PCR) for the detection of Plasmodium Falciparum (Pf) as well as Pf genotyping.  At the same time, we have identified local laboratories within high burden countries that can be utilized for the initial diagnosis and quick turnaround time testing required in trials where there is not sufficient time to ship samples to our central lab facility.  Working in this type of hybrid strategy improves result availability and reduces logistic costs for our sponsors. 

Much work to be done
Increased funding is required to meet substantial unmet needs in the fight against malaria, including treatment for children under the age of 6 months and the development of a vaccine with sufficient efficacy to move into the real-world setting. The complications and challenges of malaria prevention and treatment are being met with innovative new strategies King Tut and Genghis Khan could have never imagined.  Indeed, this is a fight with potential for great reward. Millions of lives could be affected for the better if malaria were to become a completely preventable disease.  Let us keep pressing forward in our efforts until we see malaria added to the list of diseases for which #VaccinesWork.


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References
  1. http://gizmodo.com/controversial-genetic-engineering-technology-could-elim-1790727517 
  2. http://www.who.int/mediacentre/factsheets/fs094/en/
  3. http://www.who.int/malaria/areas/drug_resistance/overview/en/
  4. http://www.nature.com/nbt/journal/v29/n12/full/nbt1211-1060b.html
  5. Arama C, Troye-Blomberg M. The path of malaria vaccine development: challenges and perspectives. J Int Med 2014;275;546-66.