Malaria vaccines since 2000: progress, priorities, products

Abstract

Malaria vaccine development entered a new era in 2015 when the pre-erythrocytic Plasmodium falciparum candidate RTS,S was favorably reviewed by the European Medicines Agency and subsequently introduced into national pilot implementation programs, marking the first human anti-parasite vaccine to pass regulatory scrutiny. Since the first trials published in 1997, RTS,S has been evaluated in a series of clinical trials culminating in Phase 3 testing, while testing of other pre-erythrocytic candidates (that target sporozoite-or liver-stage parasites), particularly whole sporozoite vaccines, has also increased. Interest in blood-stage candidates (that limit blood-stage parasite growth) subsided after disappointing human efficacy results, although new blood-stage targets and concepts may revive activity in this area. Over the past decade, testing of transmission-blocking vaccines (that kill mosquito/sexualstage parasites) advanced to field trials and the first generation of placental malaria vaccines (that clear placenta-sequestering parasites) entered the clinic. Novel antigen discovery, human monoclonal antibodies, structural vaccinology, and improved platforms promise to expand on RTS,S and improve existing vaccine candidates.

Repurposing Drugs to Fight Hepatic Malaria Parasites

“…Despite recent progress in the quest for an effective vaccine against malaria, with a particular emphasis on vaccine candidates that target the liver stage of the Plasmodium life cycle [ 240 , 241 , 242 , 243 ], such a vaccine remains elusive. As such, the need for other strategies to prevent and treat malaria remains as pressing as ever.…”

Malaria vaccine research & innovation: the intersection of IA2030 and zero malaria

“…The early promise of innovative vector control and single-dose radical cure for malaria have yet to deliver the impact needed to achieve "zero malaria". That said, steadily over the last two decades, as reviewed by Duffy and Gorres, a pipeline of vaccine candidates against the most lethal human malaria, P. falciparum, and the most prevalent, P. vivax, has been assembled 6 . Novel vaccine platforms (e.g., P. berghei sporozoite-based human vaccine candidates 7 ), better defined correlates of protection in nonhuman primates 8 , and orthogonal learnings from other mosquitotransmitted pathogens (e.g., West Nile Virus) 9 portend an even more robust pipeline of needed new tools, if adequate investments are made.…”

“…6 ). Despite decades of efforts directed against targets throughout the lifecycle, only one vaccine candidate, the pre-erythrocytic circumsporozoite (CSP)-based RTS,S/AS01 E , has advanced through licensure and pilot implementation 6 . A myriad of biological and technical barriers have been encountered; however, step-by-step, these barriers have been chipped away.…”

“…Even when pregnant women and their offspring do not have a higher risk of disease, there is an ethical rationale to evaluate at least vaccine safety pre-licensure 20 . Pregnancy malaria presents an even clearer case for prioritizing vaccine development as both mother and offspring have a well-described higher risk of disease 6 . More than two decades ago, antibodies to VAR2CSA, a member of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family, were associated with protection, identifying VAR2CSA as a promising vaccine target 21 .…”

“…More than two decades ago, antibodies to VAR2CSA, a member of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family, were associated with protection, identifying VAR2CSA as a promising vaccine target 21 . Placenta malaria vaccine (PMVs) research and innovation continues to progress 6 , including through the development of new animal models 22 and down-selection of lead PVM candidates 23 .…”