key: cord-0707155-xlm043mm
authors: Gottlieb, Robert L; Spak, Cedric W
title: The Olympiad of SARS-CoV-2 vaccinology: Fundamentals to Complement Technical Frontiers
date: 2021-01-30
journal: Clin Infect Dis
DOI: 10.1093/cid/ciab088
sha: bb79d8a271363495b8768157e3ee19cb9cf4804c
doc_id: 707155
cord_uid: xlm043mm

nan

A c c e p t e d M a n u s c r i p t

In sports, a goal is a goal. . . whether or not it was a golasso, it counts the same as long as crosses the goal line, while observing the rules of sportsmanship. Another truth from sports is that is impossible to win a game if it remains tied at 0-0. Such is our common shared objective in the fight to eradicate or control SARS-CoV-2, and the varied Covid-19 disease states wrought by this no-longer-quite-asnovel 2019 beta-coronavirus. As the novelty has worn off, we just need this virus eradicated or controlled -the more shots-on-goal, the better. Although we are fortunate that two mRNA vaccines have received FDA emergency use authorization (1, 2, 3, 4) the global community will benefit from diverse vaccine strategies to maximize vaccine production, simplify vaccine delivery, accelerate future vaccine initiatives for other SARS-family coronaviridae, and to offer excess antigenic coverage to mitigate viral escape mutations in spike protein. Olympiad, and underscores the pressing need for an alternative, practical, temperature-stable workhorse vaccine to ensure that inhabitants of each continent receive adequate protection.

Historically, polio eradication campaigns illustrate the utility and challenges of a distribution chain for traditional vaccinology approaches of the live-attenuated (Sabin-approach) and inactivated vaccine (Salk-approach), each with their relative merits and gaps. But unlike the global campaign to eradicate poliomyelitis, the development of a non-pathogenic, live-attenuated, passaged SARS-CoV-2 strain as a traditional alternative vaccinology approach is, at least for now, thwarted by our A c c e p t e d M a n u s c r i p t nascent and as-yet primitive understanding of how this disease transitions from being a viral disease to a post-viral (or virally-uncoupled) entity, with its pleiotropic and protean manifestations of Covid-19. The quest for a non-pathogenic, passaged strain being an a priori non-starter, in that light, Che and co-authors of the current study (6) provide an informed update on their phase 2a development of a traditional "killed" or inactivated virus vaccine against SARS-CoV-2 (analogous to the Salk approach), with multiple available epitopes including antigenic stimulation to both nucleocapsid as well as spike proteins.

Fundamentally, this begins with basic tissue culture to amplify and harvest live SARS-CoV-2 in a Bio-Safety 3 equivalent laboratory -a task that requires technicians with fortitude and courage. This traditional vaccine approach harvests potentially infectious plaque-forming units that are rendered inert via traditional formaldehyde and propiolactone-inactivation, purified, and delivered as an alumadjuvanted SARS-CoV-2 vaccine. This particular inactivated vaccine was harvested from a strain obtained from a single definitive SARS-CoV-2 case from western China, but offers the advantage that if the circulating strains change sufficiently, it still provides a broad range of viral nucleocapsid (N) and spike (S) epitopes from the whole, inactivated virions, as well as a pathway to recapitulate the vaccine in the unlikely event the world were to require seasonal vaccine.

The authors utilized a boosted protocol using one of two alternative schedules, delivering the second dose at either 14 or 28 days after the initial inoculation, and studied a 2:2:1 randomization of mediumdose (100 EU), high-dose (150 EU), versus placebo. Beyond collecting safety endpoints, they collected functional data with anti-S and anti-N geometric mean titers, and more critically, assessed neutralizing ability in a functional Vero-cell assay. The medium and high-dose regimen demonstrated neutralizing responses in 89 % and 96 % of subjects, respectively, in the 14-day boosted regimen, with the paired high-dose inocula performing comparably to the 28-day boosted protocol that A c c e p t e d M a n u s c r i p t demonstrated neutralizing antibody titers in 95 % of subjects in both the medium and high-dose arms.

The favorable data for the 14-day boosted regimen using high-dose inoculation would allow more rapid coverage and induction of immunity, should clinical efficacy be demonstrated in a phase 3 trial.

Ultimately, this study provides context and necessary pre-requisite data en route to a planned phase 3 trial to assess for clinical efficacy, informed by their promising initial surrogates. It is critical to note that this important contribution is looking only at humoral biomarkers and cell-culture assay of immunity without measures of cellular immunity nor clinical endpoints.

Our single-stranded RNA global opponent is a nano-sized member of the beta-coronaviridae, and is a shared nemesis to all who possess or one or more lungs. The authors have attested that they followed the tenets of the Declaration of Helsinki, followed good clinical practice, with appropriate data safety monitoring committee oversight, with voluntary participation of the subjects. As the studied cohort was aged 18-59, it remains unknown whether the same boosted protocol would remain optimal in other age groups, or in other demographic groups, but these are readily tested in a phase III trial which is clearly justified by their phase IIa data. The world awaits these next steps.

Information from the neutralizing monoclonal antibodies directed against varied epitopes of the receptor-binding domain (RBD) of the spike protein including bamlanivilab and etesevimab (Lilly) and casarivimab and imdevimab (Regeneron) as well as clinical understanding is helping us ensure that humoral therapy and vaccines do not seem to be impacted by clinically-meaningful antibodydependent enhancement or cytotoxicity, and confirmed by the interim phase 3 data from firstgeneration SARS-CoV-2 mRNA vaccines from Pfizer (1, 3) and Moderna (2, 4) encoding a homogenous spike sequence. It is likely that we will ultimately have multiple therapies and multiple vaccines. Our tools to assess innate and cellular immunity remain imperfect. We are fortunate that emerging data from the Pfizer, Moderna, and Astra Zeneca vaccines inform us that the SARS-CoV-2 A c c e p t e d M a n u s c r i p t S (spike) protein is indeed an appropriate and viable target. Nevertheless, the traditional inactivated vaccine approach hold promise as a worthy, complementary addition.

SARS-CoV-2 is a consequential and devastating virus, yet it is unlikely to be a particularly "fit," having limited genomic size and a constrained sequence space to sample for escape mutations. If spike mutations happen to decrease efficacy of spike-specific vaccine strategies, the world may require comparative efficacy data from multiple workarounds. Chimeric derivatives of mRNA or vectored vaccines encoding various different spike variant cassettes may suffice, but inactivated vaccines offer a back-up of alternative epitopes just in case. Like saline for cholera, or like a goal in sports, vaccinology does not need to be fancy… it just needs to work. The world eagerly awaits the next stepsobjective data from phase 3 trials of this, and similar, inactivated SARS-CoV-2 vaccines.

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M a n u s c r i p t