Preclinical efficacy and immunogenicity assessment to show that a chimeric Plasmodium falciparum UB05-09 antigen could be a malaria vaccine candidate.

J N Dinga,S D Gamua,S M Ghogomu,V P K Titanji

doi:10.1111/pim.12514

Abstract

SummaryAlthough it is generally agreed that an effective vaccine would greatly accelerate the control of malaria, the lone registered malaria vaccine Mosquirix™ has an efficacy of 30%‐60% that wanes rapidly, indicating a need for improved second‐generation malaria vaccines. Previous studies suggested that immune responses to a chimeric Plasmodium falciparum antigen UB05‐09 are associated with immune protection against malaria. Herein, the preclinical efficacy and immunogenicity of UB05‐09 are tested. Growth inhibition assay was employed to measure the effect of anti‐UB05‐09 antibodies on P. falciparum growth in vitro. BALB/c mice were immunized with UB05‐09 and challenged with the lethal Plasmodium yoelii 17XL infection. ELISA was used to measure antigen‐specific antibody production. ELISPOT assays were employed to measure interferon‐gamma production ex vivo after stimulation with chimeric UB05‐09 and its constituent antigens. Purified immunoglobulins raised in rabbits against UB05‐09 significantly inhibited P. falciparum growth in vitro compared to that of its respective constituent antigens. A combination of antibodies to UB05‐09 and the apical membrane antigen (AMA1) completely inhibited P. falciparum growth in culture. Immunization of BALB/c mice with recombinant UB05‐09 blocked parasitaemia and protected them against lethal P. yoelii 17XL challenge infection. These data suggest that UB05‐09 is a malaria vaccine candidate that could be developed further and used in conjunction with AMA1 to create a potent malaria vaccine.

Highlights

The recently approved malaria vaccine, MosquirixTM, which was previously called RTS,S was derived from the circumsporozoite protein (CSP)
When sera collected from mice that had survived the challenge infection for 4 months were analysed for Immunoglobulin-G levels, it was observed that the antigen-specific antibody for rUB05-09 was significantly higher than that for rUB05 and far higher than that for rUB09 (P = .0001) (Figure 3)
We have previously shown in immuno-epidemiological studies that immune responses to chimeric P. falciparum UB05-09 antigen are

Summary

| INTRODUCTION

Despite the considerable success of the global effort to control malaria, it still claimed 429 000 lives in 2015.1 the main control measures like arteminisin-based combination therapy, the use of impregnated mosquito bed nets and the targeted use of insecticides are threatened by the development and spread of drug and insecticide resistances. Blood-stage antigens have been shown to be targeted by antibodies, and this phenomenon is believed to have contributed at least in part to this naturally acquired immunity.[6] This has been demonstrated by passive transfer of immunity studies, in which the transfer of total immunoglobulins from individuals led to very substantial reductions of parasitaemia and clinical symptoms thereby implicating Immunoglobulin-G in the acquisition of protective immunity to malaria.[7]. The most studied and advanced blood-stage vaccine antigens include the merozoite surface protein 3 (MSP-3), serine repeat antigen 5 (SERA-5) and apical membrane antigen 1 (AMA1).[8] These candidates have not been efficacious in African children.[9,10]. Differential immune screening is an unbiased systems biology approach that allows for the identification of potential vaccine candidates using antibodies from semi-immune vs susceptible subjects in endemic areas.[17,18] This approach led to the identification of UB05 This was done using Plasmodium falciparum growth inhibition assays using rabbit antibodies to UB05-09 and immunization-challenge studies using the Plasmodium yoelii mouse model

Findings

| MATERIALS AND METHODS

| DISCUSSION