Evaluating Use Cases for Human Challenge Trials in Accelerating SARS-CoV-2 Vaccine Development

Nguyen, L.; Bakerlee, Christopher W; McKelvey, Tomas; Sm, Rose; Norman, Alexander John; Joseph, Nicholas; Manheim, David; McLaren, Michael R.; Jiang, Steven; Barnes, Conor F; Kinniment, Megan; Foster, Derek M.; Darton, Thomas C.; Morrison, Josh

doi:10.1093/cid/ciaa935

Cited by 25 publications

(21 citation statements)

References 24 publications

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“…However, the protective nature of both vaccine- and infection-elicited neutralizing antibodies in humans remains unproven, with animal models being used to make inferences about protection (10, 11). Human challenge trials, which could provide rapid information about the protection conferred by neutralizing antibodies (12, 13), are controversial due to the severity and unknown long-term impacts of SARS-CoV-2 infection and concerns over ethical administration of such trials (14, 15).…”

Section: Introductionmentioning

confidence: 99%

Neutralizing antibodies correlate with protection from SARS-CoV-2 in humans during a fishery vessel outbreak with high attack rate

Addetia

Crawford

Dingens

et al. 2020

Preprint

236

283

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The development of vaccines against SARS-CoV-2 would be greatly facilitated by the identification of immunological correlates of protection in humans. However, to date, studies on protective immunity have only been performed in animal models and correlates of protection have not been established in humans. Here, we describe an outbreak of SARS-CoV-2 on a fishing vessel associated with a high attack rate. Predeparture serological and viral RT-PCR testing along with repeat testing after return to shore was available for 120 of the 122 persons on board over a median follow-up of 32.5 days (range 18.8 to 50.5 days). A total of 104 individuals had an RT-PCR positive viral test with Ct <35 or seroconverted during the follow-up period, yielding an attack rate on board of 85.2% (104/122 individuals). Metagenomic sequencing of 39 viral genomes suggested the outbreak originated largely from a single viral clade. Only three crewmembers tested seropositive prior to the boat's departure in initial serological screening and also had neutralizing and spike-reactive antibodies in follow-up assays. None of these crewmembers with neutralizing antibody titers showed evidence of bona fide viral infection or experienced any symptoms during the viral outbreak. Therefore, the presence of neutralizing antibodies from prior infection was significantly associated with protection against re-infection (Fisher's exact test, p=0.002).

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Section: Introductionmentioning

confidence: 99%

Neutralizing antibodies correlate with protection from SARS-CoV-2 in humans during a fishery vessel outbreak with high attack rate

Addetia

Crawford

Dingens

et al. 2020

Preprint

236

283

View full text Add to dashboard Cite

show abstract

“…The potential for benefits from challenge trials are largely societal. By contrast, the risks and burdens of challenge trials—including infection-related risks, prolonged period of biocontainment and possible trial vaccine or treatment side effects—fall largely on volunteers 9 . These risks and burdens (which are heightened by uncertainty about COVID-19 disease outcomes) coupled with the absence of obvious direct benefits for volunteers have led some bioethicists to suggest that challenge trials using the novel coronavirus may be unethical 10,11,12 .…”

Section: Tablementioning

confidence: 99%

Characterizing altruistic motivation in potential volunteers for SARS-CoV-2 challenge trials

Schmit²,

Darton

et al. 2021

Preprint

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In human challenge trials, volunteers are deliberately infected with a pathogen to accelerate vaccine development and answer key scientific questions. In the U.S., preparations for challenge trials with the novel coronavirus are complete, and in the U.K., challenge trials have recently begun. However, ethical concerns have been raised about the potential for invalid consent or exploitation. These concerns largely reflect worries that challenge trial volunteers may be unusually risk-seeking or too economically vulnerable to refuse the payments these trials provide, rather than being motivated primarily by altruistic goals. We conducted the first large-scale survey of intended human challenge trial volunteers and found that SARS-CoV-2 challenge trial volunteers exhibit high levels of altruistic motivations without any special indication of poor risk perception or economic vulnerability. Findings indicate that challenge trials with the novel coronavirus can attract volunteers with background conditions, attitudes, and motivations that should allay key ethical concerns.

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“…While the changing situation has led some to question the need for HCTs, others have defended their usefulness (Turk, 2021). The usefulness is because HCTs can be used to answer a variety of questions (Nguyen et al, 2020), including many not addressed by the availability of current vaccines (Steuwer, Jamrozik, & Eyal, 2021; Ducarmon, Kuijper, & Olle, 2021). However, two ethical problems have been raised which stand in the way of conducting HCTs for SARS-CoV-2 infection.…”

Section: Introductionmentioning

confidence: 99%

Exploring Risks of Human Challenge Trials for COVID-19

Manheim

Więcek²,

Schmit³

et al. 2020

Preprint

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Human Challenge Trials (HCTs) are a potential method to accelerate development of vaccines and therapeutics. However, HCTs for COVID-19 pose ethical and practical challenges, in part due to the unclear and developing risks. In this paper, we introduce an interactive model for exploring some risks of a SARS-COV-2 dosing study, a prerequisite for any COVID-19 challenge trials. The risk estimates we use are based on a Bayesian evidence synthesis model which can incorporate new data on infection fatality rates (IFRs) to patients, and infer rates of hospitalization. We have also created a web tool to explore risk under different study design parameters and participant scenarios. Finally, we use our model to estimate individual risk, as well as the overall mortality and hospitalization risk in a dosing study.Based on the Bayesian model we expect IFR for someone between 20 and 30 years of age to be 17.5 in 100,000, with 95% uncertainty interval from 12.8 to 23.6. Using this estimate, we find that a simple 50-person dosing trial using younger individuals has a 99.1% (95% CI: 98.8% to 99.4%) probability of no fatalities, and a 92.8% (95% CI: 90.3% to 94.6%) probability of no cases requiring hospitalization. However, this IFR will be reduced in an HCT via screening for comorbidities, as well as providing medical care and aggressive treatment for any cases which occur, so that with stronger assumptions, we project the risk to be as low as 3.1 per 100,000, with a 99.85% (95% CI: 99.7% to 99.9%) chance of no fatalities, and a 98.7% (95% CI: 97.4% to 99.3%) probability of no cases requiring hospitalization.

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Evaluating Use Cases for Human Challenge Trials in Accelerating SARS-CoV-2 Vaccine Development

Cited by 25 publications

References 24 publications

Neutralizing antibodies correlate with protection from SARS-CoV-2 in humans during a fishery vessel outbreak with high attack rate

Neutralizing antibodies correlate with protection from SARS-CoV-2 in humans during a fishery vessel outbreak with high attack rate

Characterizing altruistic motivation in potential volunteers for SARS-CoV-2 challenge trials

Exploring Risks of Human Challenge Trials for COVID-19

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