SARS-CoV-2 Human Challenge Studies — Establishing the Model during an Evolving Pandemic

Rapeport, Garth; Smith, Emma; Gilbert, Anthony; Catchpole, Andrew; McShane, Helen; Chiu, Christopher

doi:10.1056/nejmp2106970

Cited by 43 publications

(51 citation statements)

References 5 publications

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“…Notably, in all cases, the 3 SARS-CoV-2 LAV candidates were more attenuated than a natural SARS-CoV-2 isolate, with rSARS-CoV-2 Δ3a/Δ7b being the most attenuated virus and rSARS-CoV-2 Δ3a/Δ7a the most virulent; and rSARS-CoV-2 Δ3a/Δ6 having an intermediate phenotype. It is worth noting that the K18 hACE2 transgenic mouse model is highly sensitive to SARS-CoV-2 infection and may not represent reflections observed in other animal models, or humans [31][32][33][34] .…”

Section: Discussionmentioning

confidence: 99%

Immunization with recombinant accessory protein-deficient SARS-CoV-2 protects against lethal challenge and viral transmission

Park

Chiem

et al. 2022

Preprint

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Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to a worldwide Coronavirus Disease 2019 (COVID-19) pandemic. Despite high efficacy of the authorized vaccines, protection against the surging variants of concern (VoC) was less robust. Live-attenuated vaccines (LAV) have been shown to elicit robust and long-term protection by induction of host innate and adaptive immune responses. We sought to develop a COVID-19 LAV by generating 3 double open reading frame (ORF)-deficient recombinant (r)SARS-CoV-2 simultaneously lacking two accessory open reading frame (ORF) proteins (ORF3a/ORF6, ORF3a/ORF7a, and ORF3a/ORF7b). Here, we report that these double ORF-deficient rSARS-CoV-2 have slower replication kinetics and reduced fitness in cultured cells as compared to their parental wild-type (WT) counterpart. Importantly, these double ORF-deficient rSARS-CoV-2 showed attenuation in both K18 hACE2 transgenic mice and golden Syrian hamsters. A single intranasal dose vaccination induced high levels of neutralizing antibodies against different SARS-CoV-2 VoC, and also activated viral component-specific T-cell responses. Notably, the double ORF-deficient rSARS-CoV-2 were able to protect, as determined by inhibition of viral replication, shedding, and transmission, against challenge with SARS-CoV-2. Collectively, our results demonstrate the feasibility to implement these double ORF-deficient rSARS-CoV-2 as safe, stable, immunogenic and protective LAV for the prevention of SARS-CoV-2 infection and associated COVID-19 disease.

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Section: Discussionmentioning

confidence: 99%

Immunization with recombinant accessory protein-deficient SARS-CoV-2 protects against lethal challenge and viral transmission

Park

Chiem

et al. 2022

Preprint

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“…Human challenge studies are a potentially rapid method to directly measure VE SUSC and VE SYMP, and to indirectly estimate VE INF using viral load, as each participant would contribute to the study endpoints. Human challenge studies have been widely used to better understand the natural history and treatment of various infections including malaria [67], influenza [68][69][70], RSV [71], and most recently, SARS-CoV-2 [72]. This approach could potentially be completed in fewer participants within 2-3 months, depending on the selected time between vaccination and viral challenge.…”

Section: Discussionmentioning

confidence: 99%

Mathematical Modeling of Vaccines That Prevent SARS-CoV-2 Transmission

Swan

Goyal

Bracis

et al. 2021

Viruses

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SARS-CoV-2 vaccine clinical trials assess efficacy against disease (VEDIS), the ability to block symptomatic COVID-19. They only partially discriminate whether VEDIS is mediated by preventing infection completely, which is defined as detection of virus in the airways (VESUSC), or by preventing symptoms despite infection (VESYMP). Vaccine efficacy against transmissibility given infection (VEINF), the decrease in secondary transmissions from infected vaccine recipients, is also not measured. Using mathematical modeling of data from King County Washington, we demonstrate that if the Moderna (mRNA-1273QS) and Pfizer-BioNTech (BNT162b2) vaccines, which demonstrated VEDIS > 90% in clinical trials, mediate VEDIS by VESUSC, then a limited fourth epidemic wave of infections with the highly infectious B.1.1.7 variant would have been predicted in spring 2021 assuming rapid vaccine roll out. If high VEDIS is explained by VESYMP, then high VEINF would have also been necessary to limit the extent of this fourth wave. Vaccines which completely protect against infection or secondary transmission also substantially lower the number of people who must be vaccinated before the herd immunity threshold is reached. The limited extent of the fourth wave suggests that the vaccines have either high VESUSC or both high VESYMP and high VEINF against B.1.1.7. Finally, using a separate intra-host mathematical model of viral kinetics, we demonstrate that a 0.6 log vaccine-mediated reduction in average peak viral load might be sufficient to achieve 50% VEINF, which suggests that human challenge studies with a relatively low number of infected participants could be employed to estimate all three vaccine efficacy metrics.

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“…The UK was the first and remains the only country in the world to commence COVID-19 human challenge studies [9] . The UK Specialist REC reviewed and approved “ A Dose Finding Human Experimental Infection Study in Health Subjects Using a GMP-produced SARS-CoV-2 Wild Type Strain ” (COHVIC), the first SARS-CoV-2 human challenge study.…”

Section: Covid-19 Human Challenge Studiesmentioning

confidence: 99%

“…The rapid improvement in knowledge about SARS-CoV-2 and interventions against it, as well as the evolution of the virus over time, has required researchers, regulators and policymakers to re-evaluate the potential scientific justification of COVID-19 human challenge studies on a regular basis. These developments have included the approval and rapid distribution of highly efficacious vaccines [6] ; the emergence of virus variants of concern [13] , [14] ; the development of therapeutic agents [15] ; and the potential post-acute health impacts of COVID-19 [9] , [16] , [17] . Amidst multiple developments in the COVID-19 pandemic, dynamic and continued reassessment of whether the potential benefits of SARS-CoV-2 human challenge studies outweigh risk is required.…”

Section: Preparing For the Futurementioning

confidence: 99%