COVID-19 Vaccines: "Warp Speed" Needs Mind Melds, Not Warped Minds

Abstract

In this review, we address issues that relate to the rapid "Warp Speed" development of vaccines to counter the COVID-19 pandemic. We review the antibody response that is triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of humans and how it may inform vaccine research. The isolation and properties of neutralizing monoclonal antibodies from COVID-19 patients provide additional information on what vaccines should try to elicit. The nature and longevity of the antibody response to coronaviruses are relevant to the potency and duration of vaccine-induced immunity. We summarize the immunogenicity of leading vaccine candidates tested to date in animals and humans and discuss the outcome and interpretation of virus challenge experiments in animals. By far the most immunogenic vaccine candidates for antibody responses are recombinant proteins, which were not included in the initial wave of Warp Speed immunogens. A substantial concern for SARS-CoV-2 vaccines is adverse events, which we review by considering what was seen in studies of SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV) vaccines. We conclude by outlining the possible outcomes of the Warp Speed vaccine program, which range from the hoped-for rapid success to a catastrophic adverse influence on vaccine uptake generally.

Keywords: COVID-19; RBD; S-protein; SARS-CoV-2; Warp Speed; animal models; neutralizing antibodies; serology; vaccines.

FIG 1

The SARS-CoV-2 S-protein. (A) Schematic of the S-protein showing the S1 and S2 domains and the RBD. The soluble S-protein ends at the engineered truncation point. The areas colored in gray indicate the transmembrane and intracytoplasmic domains that are present in the full-length S-protein on virions. The most commonly used immunogens are the soluble S-protein, the S1 domain, and the RBD, although some nucleic acid and viral vector constructs are based on the full-length S-protein. (B) Structure-based representation of the S-protein trimer viewed from above and the side, as indicated. The protein surface is in gray, with the ACE2 binding site on the RBD highlighted in aquamarine. On one protomer, the RBD is shown in the “up” position, while on the other two it is in the “down” position, as indicated. Glycans are colored according to the scale, based on their oligomannose content. Adapted from reference under a CC BY 4.0 license.

FIG 2

Magnitudes of S-protein binding antibody (ELISA) and NAb responses in COVID-19 cases and vaccinated humans and animals. (A to C) Anti-S protein (open symbols) and anti-RBD (closed symbols) endpoint titers. (D to F) NAb midpoint titers (ID₅₀) from PV assays (open symbols) and RV assays (closed symbols). In each plot, the titers for individual study subjects, the median values for a test group, or the range recorded in a study cohort are presented. The data in panels A and D are derived from virus-infected humans and nonhuman primates (NHPs) and show titers obtained in the first several weeks post symptoms. (B, C, E and F) Peak responses to S-protein- or RBD-based vaccines in humans and animals. (B and E) Studies in humans and NHPs; (C and F) studies in small animals (mice, guinea pigs, and rabbits), as indicated by the labels on the x axes. In the small-animal experiments, the immunogens used are grouped together from left to right as follows: DNA, RNA, adenovirus vectors, killed virus, recombinant S-protein, or RBD-protein. Data relating to SARS-CoV-2 are in red, SARS-CoV-1 in blue, and MERS-CoV in green. For experimental details, the cited papers listed on the x axes should be consulted. Assay methodologies vary between studies, which reduces the comparability of the resulting data sets. However, we judge that broad trends can still be seen. We have only included binding antibody endpoint titers and NAb midpoint (ID₅₀) titers on the plots, excluding other methods of data representation. Multiple other papers cited in the text report on antibody responses to the S-protein (or other antigens) in infected humans but do so using other formats; in those papers, the responses usually span a >1,000-fold range. We note that NAb endpoint titers were presented in the following papers and the unrecorded midpoint titer values would probably be >100-fold lower: endpoint titer range <10 to ∼300 for MERS-CoV DNA vaccine-immunized humans (103); median endpoint titers of 34 and 46 in RV and PV assays, respectively, for Ad5 vaccine-immunized humans (94); endpoint titer range of 5 to 60 for SARS-CoV-2-infected rhesus macaques (128); median endpoint titer of ∼40 for ChAdOx1-immunized rhesus macaques (131).

FIG 3

SARS-CoV-2 vaccine responses and their relationships to protective immunity. (A) The rate of decay of SARS-CoV-2 NAbs from an initial vaccine-induced peak ID₅₀ titer of 3,000 during the following year. The titer intersects the protective titer value of 300 (dotted line) after 6 months. The values chosen are hypothetical, although a titer decay to below protective levels over a 6-month period would be broadly consistent with the decline after infection with common-cold coronaviruses (65–67). (B) Variation in SARS-CoV-2 NAb titers among a cohort of vaccinated individuals and the relationship to the protective titer value of 300 (dotted line). The value of 300 is hypothetical but is consistent with values discussed in the text (e.g., see reference 62). The assay has a titer quantitation limit of 10. (Left) Peak titers immediately after the immunization schedule is completed; (right) titers 6 months later. Scenario 1, the vaccine induces a strong enough peak response for most recipients to be protected and vaccine efficacy is high; scenario 2, for a weaker vaccine, the protective threshold is initially exceeded in only half of the recipients; scenario 3, titers in only a minority of the recipients of a poorly immunogenic vaccine exceed the protective threshold. In each scenario, the 50-fold titer decay over 6 months causes far fewer of the vaccine recipients to be protected at this time. A booster immunization for the two stronger vaccines could restore immunity to protective levels in some people. As for panel A, the titer values and decay rates are hypothetical. However, the range of titers seen in an immunization cohort is consistent with published data (103, 133, 134); an ∼50-fold decrease in the SARS-CoV-1 NAb titer during a 6-month period was measured in RBD-immunized mice (62), and NAb titers induced by a MERS-CoV DNA vaccine in humans had declined by ∼50-fold within a year (103).