An estimated 216 million cases of malaria occurred worldwide, leading to an estimated 445,000 deaths in 2016 (WHO). Children under the age of five in sub-Saharan Africa are especially vulnerable, accounting for approximately two thirds of all global deaths due to malaria. Plasmodium falciparum is the most prevalent malaria parasite in sub-Saharan Africa, accounting for 99% of estimated malaria cases in 2016.
In Malaysia, malaria risk exists in limited foci in the states of Sabah and Sarawak and the central areas of Peninsular Malaysia. The risk is present in the mountainous interiors of the states of Kedah, Perak, Kelantan Pahang, Selangor and Negeri Sembilan. Urban and coastal areas of peninsular Malaysia, including the island of Penang are risk free.
Malaysia is very close to reaching the WHO target of human malaria elimination. MOH has targeted Malaysia to be declared a human indigenous malaria free nation by the WHO by 2020. In 2017, only 85 people were infected with human malaria. With the Malaria Elimination Programme in place, malaria cases decreased from 4,164 in 2011 to zero cases in 2018. However, since 2008, Malaysia has reported more than 15,000 cases of P. knowlesi infection and about 50 deaths. Infections in 2017 alone totalled 3,600. The risk of P. knowlesi infection, which is now known as the fifth human malaria species, is closely tied to rapid deforestation. P. knowlesi is increasingly reported elsewhere in Southeast Asia, including Indonesia, Thailand, Vietnam, and Myanmar. There is currently no vaccine against P. knowlesi in the pipeline. The human malaria vaccine does not protect against P. knowlesi malaria.
Currently no vaccine against human malaria is registered. More than 20 vaccine candidates are currently being evaluated in clinical trials or in advanced preclinical phases. Various vaccine concepts for human malaria vaccine candidates include:
- Sporozoite subunit vaccines: pre-erythrocytic vaccines that prevent infection
- Whole sporozoite vaccines
- Liver-stage subunit vaccines
- Blood-stage vaccines: limit infection and disease
- Transmission-blocking vaccines: interrupt the spread of infection
Recent progress has been made with the completion of a Phase 3 trial of the RTS,S/AS01 candidate vaccine and review by the European Medicines Agency and WHO. The RTS,S/AS01 (commercial name Mosquirix), a sporozoite subunit vaccine, is currently at Phase 4 trial. It targets the CS protein on the sporozoite of P. falciparum. It is a combination of CS protein (PfCSP), hepatitis B surface antigen, and AS01 adjuvant which create a more robust immune response than nature.
The Phase 3 trial of RTS,S/AS01 was conducted over 5 years (2009–2014) in 11 sites in 7 sub-Saharan African countries: Burkina Faso, Gabon, Ghana, Kenya, Malawi, Mozambique and the United Republic of Tanzania. The trial enrolled approximately 15,500 infants and young children, and showed protective efficacy against clinical malaria. Two safety signals (meningitis, cerebral malaria) were recorded, for which the cause is unknown and a confirmed risk of febrile convulsions within 7 days of vaccination was noted in the 5–17 month age category, all of which resolved without long-term sequelae.
In January 2016, WHO published its position paper for this first malaria vaccine, officially adopting the joint recommendation by SAGE and the Malaria Policy Advisory Committee (MPAC). WHO recommends pilot implementation of vaccine in selected areas in sub-Saharan Africa in order to generate critical evidence for potential wider scale application. Three countries (Ghana, Kenya, Malawi) were selected to participate in pilot program called the Malaria Vaccine Implementation Program (MVIP), to be implemented from 2017 to 2022. The MVIP aims to support the introduction of the vaccine through routine immunisation program and to evaluate the outstanding questions related to the public health use of the vaccine. Preparatory work for regulatory approval, vaccine introduction and pilot evaluation has been initiated. The MVIP consists of three components:
- Vaccine introduction: National immunisation programmes in Ghana, Kenya, and Malawi will lead the pilot introduction of the malaria vaccine in areas with moderate to high malaria transmission.
- Pilot evaluation: A master protocol has been developed to evaluate:
i. the programmatic feasibility of delivering RTS,S/AS01 with new immunisation contacts, including the fourth dose in the second year of life;
ii. the vaccine’s impact on mortality and
iii. the vaccine’s safety in the context of routine immunisation, with an emphasis on meningitis and cerebral malaria.
GSK Phase 4 study: The GSK-sponsored observational Phase 4 studies to further assess vaccine safety, effectiveness and impact in routine use. The WHO-led pilot evaluation has been designed to complement the GSK Phase 4 study that will take place in a small sub-set of the pilot areas.
Another candidate malaria vaccine is the PfSPZ vaccine developed by Sanaria. It is made of non-replicating irradiated whole sporozoites and and also targets pre-erythrocytic stage of the parasite. It was granted fast track designation by the U.S. Food and Drug Administration in September 2016.
Evidence for Effectiveness
In the Phase 3 trial of RTS,S/AS01, among children aged 5–17 months who received three doses of vaccines administered at 1- month intervals, followed by a fourth dose 18 months later, the vaccine reduced malaria episodes by 39%, equivalent to preventing nearly 4 in 10 malaria cases. In addition, the 4-dose vaccine schedule reduced severe malaria by 32% in this age group, with reductions in malaria hospitalisations (37%), all-cause hospitalisation (15%) and severe anaemia (62%). Blood transfusions were reduced by 29%. The protective benefit against severe malaria was absent among children who did not receive the fourth dose.
Protection was found to be age-dependent, where vaccine efficacy was low in the younger (6–12 weeks) age category in this Phase 3 trial. Due to the low efficacy, the use of the vaccine in this age category is not recommended.
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