Sterile Protection against Plasmodium knowlesi in Rhesus Monkeys from a Malaria Vaccine: Comparison of Heterologous Prime Boost Strategies

Abstract

Using newer vaccine platforms which have been effective against malaria in rodent models, we tested five immunization regimens against Plasmodium knowlesi in rhesus monkeys. All vaccines included the same four P. knowlesi antigens: the pre-erythrocytic antigens CSP, SSP2, and erythrocytic antigens AMA1, MSP1. We used four vaccine platforms for prime or boost vaccinations: plasmids (DNA), alphavirus replicons (VRP), attenuated adenovirus serotype 5 (Ad), or attenuated poxvirus (Pox). These four platforms combined to produce five different prime/boost vaccine regimens: Pox alone, VRP/Pox, VRP/Ad, Ad/Pox, and DNA/Pox. Five rhesus monkeys were immunized with each regimen, and five Control monkeys received a mock vaccination. The time to complete vaccinations was 420 days. All monkeys were challenged twice with 100 P. knowlesi sporozoites given IV. The first challenge was given 12 days after the last vaccination, and the monkeys receiving the DNA/Pox vaccine were the best protected, with 3/5 monkeys sterilely protected and 1/5 monkeys that self-cured its parasitemia. There was no protection in monkeys that received Pox malaria vaccine alone without previous priming. The second sporozoite challenge was given 4 months after the first. All 4 monkeys that were protected in the first challenge developed malaria in the second challenge. DNA, VRP and Ad5 vaccines all primed monkeys for strong immune responses after the Pox boost. We discuss the high level but short duration of protection in this experiment and the possible benefits of the long interval between prime and boost.

Baculovirus-Vectored Multistage Plasmodium vivax Vaccine Induces Both Protective and Transmission-Blocking Immunities against Transgenic Rodent Malaria Parasites

“…However, a major concern for the development of multivalent vaccines is the potential for vaccine interference which would be associated with poor immune responses (35). In fact, it has been reported that immune responses to the individual components of multiantigen malaria vaccines can potentially be suppressed by immune interference (36)(37)(38)(39)(40)(41)(42)(43). The BDES-Pvs25-PvCSP-G vaccine successfully induced high Pvs25-, PvCSP(Sal)-, and PvCSP(PNG) repeatspecific Ab titers, suggesting an absence of immune interference.…”

Immunization with Apical Membrane Antigen 1 Confers Sterile Infection-Blocking Immunity against Plasmodium Sporozoite Challenge in a Rodent Model

“…Several studies in mice, nonhuman primates, and humans have investigated the protective capacity of multiantigen vaccines against sporozoite challenge, with no conclusive results. In the P. knowlesi nonhuman primate model, DNA prime/poxvirus boost immunization with a combination of four candidate vaccine antigens, i.e., circumsporozoite protein (CSP), sporozoite surface protein 2 (SSP2), AMA-1, and the 42-kDa fragment of merozoite surface protein 1 (MSP1 42 ), led to self-limited, lowlevel parasitemia in 60% to 80% of rhesus monkeys (47,48). In humans, a virosome-based vaccine comprising peptides representing the P. falciparum CSP B cell repeat and the semiconserved loop I of domain III of AMA-1 induced very limited blood-stage protection (manifested primarily as a delay in development of parasitemia in 1 of 12 volunteers) (49).…”

Combining Liver- and Blood-Stage Malaria Viral-Vectored Vaccines: Investigating Mechanisms of CD8+ T Cell Interference

“…This study found that AMA1-specific Ab responses are reduced when AMA1 is coadministered with either RTS,S or the 42-kDa C terminus of MSP1 (MSP1 42 ). A substantial body of work has also been carried out investigating mixtures of DNA and poxvirus vaccines encoding four to nine malaria Ags in mice and macaques (16)(17)(18)(19)(20)(21). This work highlighted the issue of antigenic competition in multicomponent malaria vaccine formulations and demonstrated that immune interference may be complex and Ag dependent.…”