The future of malaria vaccines
By World Healthcare Journal-
New malaria vaccines aim to move beyond reducing malaria disease and death to the longer-term goals of elimination and eradication, says Dr Bahijja Raimi-Abraham, Lecturer in Pharmaceutics at Kings College London, and Professor Trevor M Jones, founder member of Medicines for Malaria.
Malaria (a vector borne disease) is a life-threatening parasitic disease caused by the protozoan parasite – Plasmodium. In humans, malaria is caused by five different parasite species of Plasmodium: mainly Plasmodium falciparum (most lethal in humans)predominantly found in sub-Saharan Africa and P.vivax (cause of recurring or benign malaria that can cause fatalities), mainly found in in South America And Southeast Asia. The other species are P.malariae(also causes recurring malaria but not as dangerous as P.vivax, also called quartan malaria) P.ovale and P.knowlesi (primate malaria).
The human malaria parasites are transmitted to people through the bites of infected female anopheles mosquitoes. Sporozoites are injected with saliva by the mosquito (transmission) travel via the blood into the liver where they develop into schizonts (human liver-stage malaria) which then burst and release daughter parasites “merozoites” into the blood (human blood stage malaria) leading to the clinical symptoms of malaria. According to the World Health Organization (WHO), in 2017 there were an estimated 219 million malaria cases in 87 countries with an estimated death toll at 435,000. The WHO African Region was home to approximately 92% of the malaria cases and 93% of malaria deaths.
Developing new therapeutics
In recent times, the treatment of malaria has been hampered by drug resistance, indicating a serious need to develop new therapeutics and new approaches which can overcome this phenomenon. There are several national malaria control and elimination programmes that exist globally which aim to reduce malaria related cases and fatalities, and to reduce malaria transition to a level where malaria is no longer a public health problem. The WHO Global Malaria Programme (GMP) is responsible for coordinating the WHO's global efforts to control and eliminate malaria. The WHO, in collaboration with the Roll Back Malaria (RBM) Partnership, has provided support to malaria endemic countries to conduct systematic national malaria programme reviews (MPRs).
For centuries malaria was endemic in many countries but has been virtually eliminated in a large number of countries by eradicating the mosquito vector. In 2016, the WHO identified 21 countries with the potential to achieve zero indigenous cases of malaria by 2020 which formed the E-2020 initiative. In 2011, Paraguay reported its last case of malaria and was officially certified by the WHO malaria certification process to be malaria-free, becoming the first country in the Americas to be granted this status in 45 years. Malaria elimination has been achieved by improving awareness and hygiene and(mainly) by spraying pesticides in areas harbouring the mosquito. The use of pesticide impregnated bed nets continues to be an effective method of reducing transmission in those countries in which malaria is still a major burden.
The Medicines for Malaria Venture (MMV) was established in 1999 as a Public Private Partnership Between the Pharmaceutical Industry and Academia, largely funded by The Bill and Melinda Gates Foundation, to discover and develop low cost, few dose, new drugs and drug combinations in a “not for profit” arrangement. Ten such products have been successfully launched. The current portfolio consists of 29 projects at various stages of development, four of which are at late (Phase III) stage. MMV funding is distributed to projects via a highly competitive annual call for proposals. Their current portfolio includes compounds that have therapeutic action at all points in the parasite life cycle. MMV is able to progress a compound through partnerships from drug discover through to clinical studies, regulatory approval and finally to the patient. Whilst new projects are of interest to MMV, older projects that failed to reach regulatory approval but have potential as still considered such as the 8-aminoquinoline compound tafenoquine. Tafenoquine was approved by the Food and Drug Administration (FDA) in 2018 under Priority Review As a result of a collaboration between MMV and GSK. Krintafel (branded name) is approved the radial cure (prevention of relapse) of P. vivax malaria patients aged 16 years and older who are receiving appropriate antimalarial therapy for acute P.vivax infection. Krintafel is the first new treatment for preventing relapse of P.vivax to be licensed in over 60 years.
Immunity and malaria
Our immune system protects us from invading pathogenic microorganisms and cancer. Immunity is the state of protection from an infectious disease and has both an innate (less specific) and an adaptive (more specific) component. Innate immunity provides a rapid non pathogen specific response and is our first line of defence against an infection. Innate immunity does not have a memory nor does it offer long lasting immunity. Adaptive immunity on the other hand offers a pathogen specific mediated two staged immune response. The initial effector response (stage one) eliminates the invading pathogen whilst the later re-exposure of the same invading pathogen induces a memory response with a more rapid immune reaction which eliminates the invading pathogen and prevents disease (stage two).
A vaccine is a biological preparation that improves immunity (i.e. the state of protection from infectious disease) to a specific disease. A vaccine typically contains an agent that resembles the disease-causing microorganism. This agent is often produced from a killed or weakened form of the microorganism or could also be one of its toxins or surface proteins. This agent triggers an immune response so that the immune system will be able to more easily recognise and destroy the microorganism when it encounters it later.
Immunity to malaria is not an absolute, protective, sterilising immunity, but rather a more suppressive type. Individuals from malaria-endemic areas are repeatedly exposed to the parasite and can develop a relative immunity that inhibits parasite multiplication, rendering the individual an asymptomatic carrier with very low densities of parasites in the blood, which do not cause any harm. The time to develop such immunity depends on the level of transmission and the individual’s exposure to malaria infection. In highly endemic (holoendemic)areas, children over five rarely suffer acute malaria, whereas in areas with less endemicity, acute malaria is common also in older children. It is important to note that in areas of low endemicity or epidemic outbreaks, immunity may never develop.
An individual who has grown up in an endemic area but has lived for long periods in a non-endemic country will lose this type of immunity. When they return to their countries of origin, often to visit friends and relatives, they form a high-risk group for developing malaria and often do not consider taking prophylactics.
Malaria Vaccine Roadmap
Originally launched at the 2006 (later updated in 2013) WHO Global Vaccine Research Forum and supported by the Malaria Vaccine Funders Group, the Malaria Vaccine Technology Roadmap formed a strategic framework that underpins the activities of the global malaria vaccine research and development(R&D) community. The Roadmap has as its vision the development and licensing of safe and effective vaccines that prevent disease and death, and prevent transmission of the malaria parasite to enable elimination and eventual eradication of the disease.
The Roadmap called for the development of vaccines and outlined a path towards licensing vaccines targeting P. falciparum and P. vivax by 2030. It encompasses two objectives: i) developing malaria vaccines with protective efficacy of at least 75% against clinical malaria and ii) developing malaria vaccines that reduce transmission of the parasite in order to substantially reduce the incidence of human malaria infection. A malaria vaccine’s desired actions can take place at several points during the life cycle of the parasite. The most significant challenge still faced is a lack of understanding of the specific immune responses associated with protection against malaria. There are three main types of malaria vaccines that can be developed:
Pre-erythrocytic vaccine candidates aim to protect against the early stage of malaria infection ie. the stage at which the parasite enters or matures in an infected person’s liver cells.
Blood-stage vaccine candidates target the malaria parasite at its most destructive stage i.e.the rapid replication of the organism in human red blood cells. Blood-stage vaccines do not aim to block all infection.
Transmission-blocking vaccine (TBV) candidates seek to interrupt the life cycle of the parasite by inducing antibodies that prevent the parasite from maturing in the mosquito after it takes a blood meal from a vaccinated person. TBV candidates aim to prevent mosquitoes from becoming infected by malaria-causing parasites when they feed on infected people.
The RTS,S (trade name Mosquirix), is an anti-infection vaccines that aims to trigger the immune system to defend against the relevant malaria parasite strain as soon as it enters a person’s bloodstream or infects liver cells. This should then prevent the parasite from infecting, maturing, and multiplying in the liver, so that there are fewer or ideally no parasites to re-enter the bloodstream and affect red blood cells, and therefore triggering symptoms of malaria. Despite this advance in developing a vaccine for malaria, the injection should be regarded as a pioneer, not a panacea. In a large clinical study, it prevented only about four in 10 malaria cases among children which required four doses at various time intervals. The malaria vaccine was recommended by the WHO for implementation under the malaria vaccine implementation programme (MVIP) for pilot introduction in selected areas in three African countries namely Malawi, Ghana and Kenya. On April 23rd 2019 vaccinations began in Malawi and in Ghana on April 30th 2019. Kenya is expected to introduce the vaccine in the coming weeks. The development of RTS,S was led by GSK over a 30 year period with GSK collaborating with the PATH Malaria Vaccine Initiative in 2001 to continue developing RTS,S.
PATH MVI strategy for 2nd generation of malaria vaccine
The PATH Malaria Vaccine Initiative (MVI) research and development strategy represents a multi-pronged approach aimed at developing the next-generation malaria vaccine that would support efforts to move beyond reducing malaria disease and death to the longer-term goals of elimination and eradication. MVI’s research and development efforts has focused on two priority areas: vaccines that prevent infection, and those that block or interrupt transmission.
The MVI has also evaluated potential vaccines that would interrupt the cycle of parasite transmission between mosquitoes and humans. The benefit of such a vaccine to the person vaccinated would be delayed. This type of vaccine would allow for community immunity to a susceptible population by significantly limiting the spread of the infection.
While highly efficacious blood-stage vaccines have the potential to prevent humans from being infectious to mosquitoes therefore serving a role in elimination, these vaccine types are mainly being developed to decrease the number of parasites in the blood, therefore reducing the severity of malaria. Such vaccines could be combined with pre-erythrocytic vaccine to further boost its effectiveness.
Professor Trevor M Jones, visiting professor at King’s College London, founder member of the Medicines for Malaria Venture (MMV).
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