Assessment of Humoral Immune Responses to Blood-Stage Malaria Antigens following ChAd63-MVA Immunization, Controlled Human Malaria Infection and Natural Exposure

Abstract

The development of protective vaccines against many difficult infectious pathogens will necessitate the induction of effective antibody responses. Here we assess humoral immune responses against two antigens from the blood-stage merozoite of the Plasmodium falciparum human malaria parasite – MSP1 and AMA1. These antigens were delivered to healthy malaria-naïve adult volunteers in Phase Ia clinical trials using recombinant replication-deficient viral vectors – ChAd63 to prime the immune response and MVA to boost. In subsequent Phase IIa clinical trials, immunized volunteers underwent controlled human malaria infection (CHMI) with P. falciparum to assess vaccine efficacy, whereby all but one volunteer developed low-density blood-stage parasitemia. Here we assess serum antibody responses against both the MSP1 and AMA1 antigens following i) ChAd63-MVA immunization, ii) immunization and CHMI, and iii) primary malaria exposure in the context of CHMI in unimmunized control volunteers. Responses were also assessed in a cohort of naturally-immune Kenyan adults to provide comparison with those induced by a lifetime of natural malaria exposure. Serum antibody responses against MSP1 and AMA1 were characterized in terms of i) total IgG responses before and after CHMI, ii) responses to allelic variants of MSP1 and AMA1, iii) functional growth inhibitory activity (GIA), iv) IgG avidity, and v) isotype responses (IgG1-4, IgA and IgM). These data provide the first in-depth assessment of the quality of adenovirus-MVA vaccine-induced antibody responses in humans, along with assessment of how these responses are modulated by subsequent low-density parasite exposure. Notable differences were observed in qualitative aspects of the human antibody responses against these malaria antigens depending on the means of their induction and/or exposure of the host to the malaria parasite. Given the continued clinical development of viral vectored vaccines for malaria and a range of other diseases targets, these data should help to guide further immuno-monitoring studies of vaccine-induced human antibody responses.

Human vaccination against RH5 induces neutralizing antimalarial antibodies that inhibit RH5 invasion complex interactions

“…Consistent with other ChAd63-MVA malaria vaccines (43,52,63), the anti-RH5_FL serum IgG response was largely composed of IgG1 and IgG3, with moderate avidity as measured by NaSCN displacement ELISA. A study of naturally exposed individuals in Mali reported that the predominant IgG isotype detected against RH5 was IgG3 (23).…”

“…IgG antibody avidity was assessed by NaSCN displacement ELISA using previously described methodology (63), except that plates were coated with recombinant RH5_FL produced from the Drosophila S2 cells at 2 μg/ml. The concentration of NaSCN required to reduce the OD 405 (optical density measured at 405 nm)to 50% of that without NaSCN was used as a measure of avidity (IC 50 ).…”

“…The concentration of NaSCN required to reduce the OD 405 (optical density measured at 405 nm)to 50% of that without NaSCN was used as a measure of avidity (IC 50 ). Antibody isotype ELISAs were also performed using methodology described in detail elsewhere (63) with the same exception as for the avidity ELISA.…”

Viral Vector Malaria Vaccines Induce High-Level T Cell and Antibody Responses in West African Children and Infants

“…Isotype ELISAs were conducted as previously described 53 except plates were coated with 0.5 μg/mL of TRAP antigen in carbonate-bicarbonate coating buffer and left overnight at 4°C. Briefly, sera were diluted 1:100 in 0.2% BSA in PBS/Tween-20 (dilution buffer) and added in duplicate to each of six 96-well plates.…”

Characterization of posttransfusion Plasmodium falciparum infection in semi‐immune nonparasitemic patients

“…This interpretation assumes, probably incorrectly, that anti‐MSP1 is representative of all antibody specificities in a given patient. Antibodies to both MSP1 and AMA‐1 are known to be relatively protective (growth‐inhibitory activity) in semi‐immune individuals and are responsive to natural parasite stimulation, but they are unlikely to be involved in parasite clearance . A weakness of our study is that anti‐MSP‐1 is probably unrelated to parasite clearance.…”