Looking beyond COVID-19 vaccine phase 3 trials

Kim, Jerome H.; Marks, Florian; Clemens, John D.

doi:10.1038/s41591-021-01230-y

Cited by 564 publications

(490 citation statements)

References 61 publications

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“…Despite observing differences in serum neutralizing activity against authentic SARS-CoV-2 variant viruses, it remains unclear how this finding translates into effects on protection in the context of secondary infection or infection after vaccination with platforms using historical spike gene sequences. Although serum neutralizing titers are an anticipated correlate of protection 37 , this measurement does not account for Fc effector functions; Fcγ receptor or complement protein engagement by non, weakly, or strongly neutralizing antibodies that bind the SARS-CoV-2 spike protein on the surface of infected cells could confer substantial protection [38][39][40] . Also, the role of memory T or B cells in protection against variant viruses is unknown and could prevent severe infection even in the setting of compromised serum antibody responses [41][42][43] .…”

Section: Discussionmentioning

confidence: 99%

Resistance of SARS-CoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies

Chen

Zhang

Case

et al. 2021

Nat Med

903

962

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evere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the global COVID-19 pandemic infecting more than 111 million people and causing 2.4 million deaths. Clinical disease in humans ranges from asymptomatic infection to pneumonia, severe respiratory compromise, multi-organ failure and systemic inflammatory syndromes. The rapid expansion and prolonged nature of the COVID-19 pandemic and its accompanying morbidity, mortality and destabilizing socioeconomic effects have made the development of SARS-CoV-2 therapeutics and vaccines an urgent global health priority 1. Indeed, the emergency use authorization and rapid deployment of antibody-based countermeasures, including mAbs, immune plasma therapy and messenger RNA, and inactivated and viral-vectored vaccines has provided hope for curtailing disease and ending the pandemic. The spike protein of the SARS-CoV-2 virion binds the cell-surface receptor angiotensin-converting enzyme 2 (ACE2) to promote entry into human cells 2. Because the spike protein is critical for viral entry, it has been targeted for vaccine development and therapeutic antibody interventions. SARS-CoV-2 S proteins are cleaved to yield S1 and S2 fragments. The S1 protein includes the N-terminal (NTD) and receptor-binding (RBD) domains, whereas the S2 protein promotes membrane fusion. The RBD is recognized by many potently neutralizing monoclonal antibodies 3-7 , protein-based inhibitors 8 and serum antibodies 9. The current suite of antibody therapeutics and vaccines was designed with a spike protein based on strains circulating during the early phases of the pandemic in 2020. More recently, variants with enhanced transmissibility have emerged in the United Kingdom (B.1.1.7), South Africa (B.1.351), Brazil (B.1.1.248) and elsewhere with multiple substitutions in the spike protein, including in the NTD and the receptor-binding motif (RBM) of the RBD. Preliminary studies with pseudoviruses suggest that neutralization by some antibodies and immune sera may be diminished against variants expressing mutations in the spike gene 10-13. Given these

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Section: Discussionmentioning

confidence: 99%

Resistance of SARS-CoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies

Chen

Zhang

Case

et al. 2021

Nat Med

903

962

View full text Add to dashboard Cite

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“…9 The herd immunity threshold for SARS-CoV-2 is estimated at 60-83%. 10 Education of the general public by frequent communication with the scientific community is key to regain and retain trust and to ensure high vaccine uptake and herd immunity in the population.…”

Section: Sars-cov-2 Vaccines: Fast Track Versus Efficacymentioning

confidence: 99%

SARS-CoV-2 vaccines: fast track versus efficacy

Alkandari¹,

Herbert²,

Alkhalaf³

et al. 2021

The Lancet Microbe

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“…However, vaccine coverage is likely to remain insufficient to control the pandemic in most global settings for many months or years. Key implementation challenges include manufacturing delays, distribution challenges, vaccine hesitancy, and the emergence of new SARS-CoV-2 variants [75][76][77]. Hence, ongoing research into alternative prevention modalities is still warranted, including the use of chemoprophylaxis.…”

Section: Discussionmentioning

confidence: 99%

Post-exposure prophylaxis against SARS-CoV-2 in close contacts of confirmed COVID-19 cases (CORIPREV): study protocol for a cluster-randomized trial

Tan

Chan

Jüni

et al. 2021

Trials

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Background Post-exposure prophylaxis (PEP) is a well-established strategy for the prevention of infectious diseases, in which recently exposed people take a short course of medication to prevent infection. The primary objective of the COVID-19 Ring-based Prevention Trial with lopinavir/ritonavir (CORIPREV-LR) is to evaluate the efficacy of a 14-day course of oral lopinavir/ritonavir as PEP against COVID-19 among individuals with a high-risk exposure to a confirmed case. Methods This is an open-label, multicenter, 1:1 cluster-randomized trial of LPV/r 800/200 mg twice daily for 14 days (intervention arm) versus no intervention (control arm), using an adaptive approach to sample size calculation. Participants will be individuals aged > 6 months with a high-risk exposure to a confirmed COVID-19 case within the past 7 days. A combination of remote and in-person study visits at days 1, 7, 14, 35, and 90 includes comprehensive epidemiological, clinical, microbiologic, and serologic sampling. The primary outcome is microbiologically confirmed COVID-19 infection within 14 days after exposure, defined as a positive respiratory tract specimen for SARS-CoV-2 by polymerase chain reaction. Secondary outcomes include safety, symptomatic COVID-19, seropositivity, hospitalization, respiratory failure requiring ventilator support, mortality, psychological impact, and health-related quality of life. Additional analyses will examine the impact of LPV/r on these outcomes in the subset of participants who test positive for SARS-CoV-2 at baseline. To detect a relative risk reduction of 40% with 80% power at α = 0.05, assuming the secondary attack rate in ring members (p0) = 15%, 5 contacts per case and intra-class correlation coefficient (ICC) = 0.05, we require 110 clusters per arm, or 220 clusters overall and approximately 1220 enrollees after accounting for 10% loss-to-follow-up. We will modify the sample size target after 60 clusters, based on preliminary estimates of p0, ICC, and cluster size and consider switching to an alternative drug after interim analyses and as new data emerges. The primary analysis will be a generalized linear mixed model with logit link to estimate the effect of LPV/r on the probability of infection. Participants who test positive at baseline will be excluded from the primary analysis but will be maintained for additional analyses to examine the impact of LPV/r on early treatment. Discussion Harnessing safe, existing drugs such as LPV/r as PEP could provide an important tool for control of the COVID-19 pandemic. Novel aspects of our design include the ring-based prevention approach, and the incorporation of remote strategies for conducting study visits and biospecimen collection. Trial registration This trial was registered at www.ClinicalTrials.gov (NCT04321174) on March 25, 2020.

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Looking beyond COVID-19 vaccine phase 3 trials

Cited by 564 publications

References 61 publications

Resistance of SARS-CoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies

Resistance of SARS-CoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies

SARS-CoV-2 vaccines: fast track versus efficacy

Post-exposure prophylaxis against SARS-CoV-2 in close contacts of confirmed COVID-19 cases (CORIPREV): study protocol for a cluster-randomized trial

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