Table 2:

Overview of P. vivax vaccine development: challenges, problems, potential actions, and 5-year plan to overcome these impediments.

Challenges	Problem	Actions	5-year plan
Blood-stage
Clinical infection of Duffy-negative individuals	P. vivax blood-stage merozoites use alternative ligands to invade Duffy-negative individuals	Target multiple epitopes essential for merozoite invasion	Identify novel ligands that facilitate merozoite invasion of Duffy-negative individuals
Low parasitemia and asymptomatic infections (lack of febrile malaria)	Parasite’s preference for Reticulocyte and host factors masks clinical infections	Better surveillance systems i.e. detection of sub-patent parasitemia	Develop tools to culture in vitro
Pre-erythrocytic stage
Preventing/eliminating dormant hypnozoites	P. vivax hypnozoite dormancy and reactivation	Research into hypnozonticidal strategies i.e drugs, PE vaccines	Establish in vitro liver stage assays to interrogate novel antigens/ targets such as ILSDA
Sexual stage
Targeting early formation of gametocytes	P. vivax sexual reproductive efficiency	Identifying blood-stage and gametocyte vaccine targets to prevent transmission	Develop in vitro tools to facilitate gametocyte cultures
Poor immunity conferred from natural exposure	Multiple vaccine doses within a transmission season could affect vaccine efficacy	Improving on adjuvant formulation, vaccine delivery and antigen selection to develop protective immune responses	Develop a potent single dose TBV candidate
Overall challenges
Lack of P. vivax sporozoites or merozoites	Parasite availability has hampered clinical trials and basic science research.	Use of in vivo models cultivate parasites and develop CHMI models (sporozoite inoculation, mosquito-bite challenges, and blood-stage inoculation).	Increase access to parasites from endemic regions. Overcome logistical challenges of mosquito-bite challenges by inoculating IBSM to test vaccine efficacy.
Overcoming parasite immune escape mechanisms	P. vivax genetic diversity and antigenic polymorphism	Identify conserved functional epitopes of neutralization and possibly target parasite using a multiantigen vaccine approach	Generate monoclonal antibodies (mAbs) that can neutralize multiple strain as passive immunization
Scarce genetic tool kit	Forward and reverse genetics tools are limited	Use transgenic or chimeric parasites to infer functions of P. vivax genes	Develop in vitro cultures, Use NHP models
Dearth of funding for P. vivax research	Inadequate funding for P. vivax research compared to P. falciparum	Increase funding to novel P. vivax vaccine research

mAbs-Monoclonal antibodies

PE-Pre-erythrocytic

ILSDA-In vitro Liver-stage Development assay

PEV- Pre-erythrocytic vaccine

TBV-Transmission blocking vaccine

CHMI-Controlled human malaria infections

IBSM- Infected blood-stage malaria

NHP-Non-human primate