Study design issues
Since vaccine-elicited anti-SARS-CoV-2 spike antibodies may themselves
be harmful, current vaccine trial endpoints may be incorrectly chosen.
The first phase of human testing of current COVID-19 vaccines are
designed to be validated, at least partly, on immunogenicity, which is
defined as elicitation of high titers of anti-pathogen antibodies by the
vaccine. Immunogenicity measured in this way usually ignores the
function and efficacy of vaccine-elicited antibodies, and is a low bar
for vaccine candidates, which only remains in contention due to distant
historical efforts, such as attempts to develop vaccines for
encapsulated pathogens like Neisseria and Pneumococcus .
Thus, in the case of COVID-19 disease, vaccine-elicited anti-SARS-CoV-2
may be detrimental or, at least, of uncertain benefit, making their
appearance and titer a puzzling choice of milestone for vaccine
advancement. The technological improvements that have been leveraged to
produce the current SARS-CoV-2 vaccine candidates have nearly all been
platform-based: e.g. lower cost and faster manufacturing of DNA or RNA
vaccines, viral vectors, skin inoculation, etc. Accordingly, the
question in the current vaccine trial of SARS-CoV-2 spike mRNA of
whether the vaccine is immunogenic is a question entirely about the
technology platform and not a predictor of efficacy of the vaccine. As
for safety, public data on ongoing COVID-19 vaccine trials do not
disclose whether antibody-mediated immunopathology is defined as an
Adverse Event of Special Interest, and indeed several of the trials, and
nearly all the trials outside the US, restrict Adverse Event monitoring
to 28 days, which would be too soon to observe worsened COVID-19 disease
due to exposure to circulating SARS-CoV-2 viruses (Source:
clinicaltrials.gov). Accordingly, some of the current viral candidates
will almost certainly pass a Phase I immunogenicity and safety test,
even if they have significant delayed ADE or immunopathology
liabilities. Similarly, Phase III trials may be incorrectly designed if
their primary endpoint is reduction in infections rather than reduction
in immunopathologic disease. If vaccine-worsened disease is indeed a
relevant phenomenon for COVID-19 vaccines, one could easily imagine a
scenario in which infections are reduced but immunopathologic disease
incidence is not or is actually higher in vaccinees. Approval of such a
vaccine would not be in the public’s best interest.
Current data on COVID-19 vaccines show no evidence of ADE of disease.
Non-human primate studies of Moderna’s mRNA-1273 vaccine showed
excellent protection with no detectable
immunopathology11. Phase 1 trials of several vaccines
have not reported any immunopathology in subjects administered the
candidate vaccines, however these subjects were unlikely to have
encountered circulating virus yet12. Nevertheless, all
preclinical studies to date have been performed with the Wuhan or
closely related strains of the virus, while a mutant D614G virus is now
the most prevalent circulating form, and several observations suggest
that this alternative form may be antigenically distinct from the Wuhan
derived strain, not so much in composition, but in conformation of the
viral spike and exposure of neutralization
epitopes13-15. Similarly, Phase 1 and 2 clinical
trials of vaccine candidates have not been designed to capture exposure
of subjects to circulating virus after vaccination, which is when
ADE/immunopathology is designed to occur. Thus, the absence of ADE
evidence in COVID-19 vaccine data so far does not absolve investigators
from disclosing the risk of enhanced disease to vaccine trial
participants, and it remains a realistic, obvious potential risk to the
subjects.