Assessment of Immune Interference, Antagonism, and Diversion following Human Immunization with Biallelic Blood-Stage Malaria Viral-Vectored Vaccines and Controlled Malaria Infection

Abstract

Overcoming antigenic variation is one of the major challenges in the development of an effective vaccine against Plasmodium falciparum, a causative agent of human malaria. Inclusion of multiple antigen variants in subunit vaccine candidates is one strategy that has aimed to overcome this problem for the leading blood-stage malaria vaccine targets, merozoite surface protein 1 (MSP1) and apical membrane antigen 1 (AMA1). However previous studies, utilizing malaria antigens, have concluded that inclusion of multiple allelic variants, encoding altered peptide ligands (APL), in such a vaccine may be detrimental to both the priming and in vivo re-stimulation of antigen-experienced T cells. Here we analyze the T cell responses to two alleles of MSP1 and AMA1 induced by vaccination of malaria-naïve adult volunteers with bi-valent viral vectored vaccine candidates. We show a significant bias to the 3D7/MAD20 allele compared to the Wellcome allele for the 33kDa region of MSP1, but not for the 19kDa fragment or the AMA1 antigen. Whilst this bias could be caused by ‘immune interference’ at priming, the data don’t support a significant role for ‘immune antagonism’ during memory T cell re-stimulation, despite observation of the latter at a minimal epitope level in vitro. A lack of class I HLA epitopes in the Wellcome allele that are recognized by vaccinated volunteers may in fact contribute to the observed bias. We also show that controlled infection with 3D7 strain P. falciparum parasites neither boosts existing 3D7-specific T cell responses nor appears to ‘immune divert’ cellular responses towards the Wellcome allele.

Neutralising antibodies block the function of Rh5/Ripr/CyRPA complex during invasion of Plasmodium falciparum into human erythrocytes

“…This finding confirms predictions from the structural model that the inhibitory epitopes on CyRPA are masked by the binding faces of Ripr and Rh5. This was also the case for Rh5 and Ripr but to a lesser degree, perhaps suggesting that there was a level of immune interference between the three antigens when immunised as a complex, although there is a level of inter‐rabbit variation in responsiveness against any antigen so it is difficult to make conclusive statements without further studies to this effect (Elias et al, ).…”

Paths to a malaria vaccine illuminated by parasite genomics

“…When polymorphisms are broadly interspersed with conserved parts of sequences, for example within AMA1 or the P. vivax DBP, such dissection to remove polymorphic sites may not be possible, although particular formulations may still induce strong antibody responses to conserved epitopes [95,97] . Alternatively, multiple allele-specific antibodies may be generated to give protection against the range of allelic types circulating within populations, a ‘diversity-covering’ approach used for several vaccine formulations that have reached clinical trials, based on MSP1 [98] , MSP2 [99] , and AMA1 [100] , as well as allelic combinations of both MSP1 and AMA1 together [101,102] .…”

Novel Bivalent Viral-Vectored Vaccines Induce Potent Humoral and Cellular Immune Responses Conferring Protection against Stringent Influenza A Virus Challenge

“…However, delivery of multiple antigens can result in immune competition (38,39), which can be largely circumvented by administration of the viral-vectored vaccine encoded antigens to separate sites as described here. While the exact mechanisms of antigenic interference following vaccination remains unknown, this phenomenon is thought to be influenced by spatial constraints on T cells (40,41).…”