Immunogenicity of clinically relevant SARS-CoV-2 vaccines in nonhuman primates and humans

Abstract

Multiple preventive vaccines are being developed to counter the coronavirus disease 2019 pandemic. The leading candidates have now been evaluated in nonhuman primates (NHPs) and human phase 1 and/or phase 2 clinical trials. Several vaccines have already advanced into phase 3 efficacy trials, while others will do so before the end of 2020. Here, we summarize what is known of the antibody and T cell immunogenicity of these vaccines in NHPs and humans. To the extent possible, we compare how the vaccines have performed, taking into account the use of different assays to assess immunogenicity and inconsistencies in how the resulting data are presented. We also review the outcome of challenge experiments with severe acute respiratory syndrome coronavirus 2 in immunized macaques, while noting variations in the protocols used, including but not limited to the virus challenge doses. Press releases on the outcomes of vaccine efficacy trials are also summarized.

Fig. 1. The measurement of antibody binding and virus neutralization in vitro.

Blood samples are obtained from patients or experimental animals and serum is separated. (Left) Serum antibody binding is usually measured by ELISA: S proteins (blue triangles) or RBDs are immobilized in wells, S-specific antibodies (green) in titrated sera are allowed to bind, and they are then detected with labeled anti-antibodies (purple with yellow flash) (51). (Right) Neutralization is measured as antibody-mediated inhibition of viral infectivity in cell culture assays. A susceptible cell is shown with blue cytoplasm, black nucleus, and red cell membrane. PVs carry a signal gene but cannot form infectious progeny, whereas RVs cause cytopathicity (51, 52). Virus particles are shown as blue circles with triangular spikes, the latter representing the S protein as in the ELISA. The internal viral core is purple. Antibodies in green bind to the S protein on virions in suspension. Some extracellular virions are prevented from receptor binding and cellular uptake by antibody binding to the S protein. Two virions are shown in endosomes. One has antibodies bound to the S protein, which prevents fusion of the viral and endosomal membranes, thereby preventing entry of the viral core into the cytoplasm.

Fig. 2. Different kinds of binding titers.

End-point titers and ED₅₀ values are measured in ELISAs. Binding curves with different maxima, midpoints (or half-maximal values), and slopes (Hill coefficients, h) are depicted. Brown stippled lines show the derivation of ED₅₀ at half the plateau values on the y-axis values; gray stippled lines show the derivation of the end-point titers, where the curve crosses a stipulated common cutoff value; all of these titer values are read on the x axis. The ED₅₀ values are products of antibody concentration and affinity, the maxima reflect the number of antigenic epitopes, and the slopes indicate antibody heterogeneity or binding cooperativity.

Fig. 3. The quantification of neutralization.

(A) Different degrees of inhibitory reciprocal dilutions are recorded for neutralization assays (purple, ID₅₀; green, ID₈₀; blue, ID₉₀; red, ID₉₉). (B) Neutralization curves differ not only in midpoints (ID₅₀) but also in plateau of maximum neutralization (max %) and slope (Hill coefficient, h) (51, 52, 56). Token values for these three quantities are given for the black curve; one quantity at the time is varied for the other curves as indicated by the color code. Markedly different curves can therefore generate similar AUC values. The relationship between antibody binding to surface viral proteins and neutralization depends on binding strength (affinity), concentration, and the occupancy of NAb on the virion that is required for neutralization (52). What neutralizing titers are sufficient for protecting organisms from infection depends on viral dose and other factors and tends to fall in the range ID₅₀ 100 to 1000 (34, 51, 52, 56). When h = 1, the ID₉₉ value is ~100 ID₅₀. Vaccine-mediated protection in vivo not only is dominated by neutralization for many viruses but also can be influenced by non-NAb antiviral effects and cytotoxic T cell responses, as well as by innate immunity and other host factors.