RESUMEN
Multiple studies of vaccinated and convalescent cohorts have demonstrated that serum neutralizing antibody (nAb) titers correlate with protection against coronavirus disease 2019 (COVID-19). However, the induction of multiple layers of immunity after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure has complicated the establishment of nAbs as a mechanistic correlate of protection (CoP) and hindered the definition of a protective nAb threshold. Here, we show that a half-life-extended monoclonal antibody (adintrevimab) provides about 50% protection against symptomatic COVID-19 in SARS-CoV-2-naïve adults at serum nAb titers on the order of 1:30. Vaccine modeling results support a similar 50% protective nAb threshold, suggesting that low titers of serum nAbs protect in both passive antibody prophylaxis and vaccination settings. Extrapolation of adintrevimab pharmacokinetic data suggests that protection against susceptible variants could be maintained for about 3 years. The results provide a benchmark for the selection of next-generation vaccine candidates and support the use of broad, long-acting monoclonal antibodies as alternatives or supplements to vaccination in high-risk populations.
Asunto(s)
COVID-19 , Adulto , Humanos , SARS-CoV-2 , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacunación , Anticuerpos Monoclonales/uso terapéuticoRESUMEN
Multiple studies of vaccinated and convalescent cohorts have demonstrated that serum neutralizing antibody (nAb) titers correlate with protection against COVID-19. However, the induction of multiple layers of immunity following SARS-CoV-2 exposure has complicated the establishment of nAbs as a mechanistic correlate of protection (CoP) and hindered the definition of a protective nAb threshold. Here, we show that a half-life extended monoclonal antibody (adintrevimab) provides approximately 50% protection against symptomatic COVID-19 in SARS-CoV-2-naive adults at low serum nAb titers on the order of 1:30. Vaccine modeling supports a similar 50% protective nAb threshold, suggesting low levels of serum nAb can protect in both monoclonal and polyclonal settings. Extrapolation of adintrevimab pharmacokinetic data suggests that protection against susceptible variants could be maintained for approximately 3 years. The results provide a benchmark for the selection of next-generation vaccine candidates and support the use of broad, long-acting monoclonal antibodies as an alternative or supplement to vaccination in high-risk populations.
RESUMEN
The recurrent zoonotic spillover of coronaviruses (CoVs) into the human population underscores the need for broadly active countermeasures. We employed a directed evolution approach to engineer three severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies for enhanced neutralization breadth and potency. One of the affinity-matured variants, ADG-2, displays strong binding activity to a large panel of sarbecovirus receptor binding domains and neutralizes representative epidemic sarbecoviruses with high potency. Structural and biochemical studies demonstrate that ADG-2 employs a distinct angle of approach to recognize a highly conserved epitope that overlaps the receptor binding site. In immunocompetent mouse models of SARS and COVID-19, prophylactic administration of ADG-2 provided complete protection against respiratory burden, viral replication in the lungs, and lung pathology. Altogether, ADG-2 represents a promising broad-spectrum therapeutic candidate against clade 1 sarbecoviruses.
Asunto(s)
Anticuerpos Monoclonales/inmunología , Anticuerpos Antivirales/inmunología , Betacoronavirus/inmunología , Anticuerpos ampliamente neutralizantes/inmunología , SARS-CoV-2/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Enzima Convertidora de Angiotensina 2/metabolismo , Animales , Anticuerpos Monoclonales/genética , Anticuerpos Monoclonales/metabolismo , Anticuerpos Antivirales/genética , Anticuerpos Antivirales/metabolismo , Afinidad de Anticuerpos , Sitios de Unión , Sitios de Unión de Anticuerpos , Anticuerpos ampliamente neutralizantes/genética , Anticuerpos ampliamente neutralizantes/metabolismo , COVID-19/prevención & control , COVID-19/terapia , Técnicas de Visualización de Superficie Celular , Evolución Molecular Dirigida , Epítopos/inmunología , Humanos , Inmunización Pasiva , Fragmentos Fc de Inmunoglobulinas/inmunología , Ratones Endogámicos BALB C , Dominios Proteicos , Ingeniería de Proteínas , Receptores de Coronavirus/metabolismo , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/inmunología , Síndrome Respiratorio Agudo Grave/inmunología , Síndrome Respiratorio Agudo Grave/prevención & control , Síndrome Respiratorio Agudo Grave/terapia , Glicoproteína de la Espiga del Coronavirus/metabolismo , Sueroterapia para COVID-19RESUMEN
The recurrent zoonotic spillover of coronaviruses (CoVs) into the human population underscores the need for broadly active countermeasures. Here, we employed a directed evolution approach to engineer three SARS-CoV-2 antibodies for enhanced neutralization breadth and potency. One of the affinity-matured variants, ADG-2, displays strong binding activity to a large panel of sarbecovirus receptor binding domains (RBDs) and neutralizes representative epidemic sarbecoviruses with remarkable potency. Structural and biochemical studies demonstrate that ADG-2 employs a unique angle of approach to recognize a highly conserved epitope overlapping the receptor binding site. In murine models of SARS-CoV and SARS-CoV-2 infection, passive transfer of ADG-2 provided complete protection against respiratory burden, viral replication in the lungs, and lung pathology. Altogether, ADG-2 represents a promising broad-spectrum therapeutic candidate for the treatment and prevention of SARS-CoV-2 and future emerging SARS-like CoVs.