Neutralizing antibody responses over time in demographically and clinically diverse individuals recovered from SARS-CoV-2 infection in the United States and Peru: A cohort study

Shelly Karuna, Shuying Sue Li, Shannon Grant, Stephen R. Walsh, Ian Frank, Martin Casapia, Meg Trahey, Ollivier Hyrien, Leigh Fisher, Maurine D. Miner, April K. Randhawa, Laura Polakowski, James G. Kublin, Lawrence Corey, David Montefiori

People infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) experience a wide range of clinical manifestations, from asymptomatic and mild illness to severe illness and death, influenced by age and a variety of comorbidities. Neutralizing antibodies (nAbs) are thought to be a primary immune defense against the virus. Large, diverse, well-characterized cohorts of convalescent individuals provide standardized values to benchmark nAb responses to past SARS-CoV-2 infection and define potentially protective levels of immunity.

Since its emergence in late 2019, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiologic agent of Coronavirus Disease 2019 (COVID-19) [1–4], has claimed millions of lives and persists at pandemic proportions. This global threat has propelled efforts to rapidly develop, assess, and implement effective vaccines and antiviral drugs, including monoclonal antibodies (mAbs), for treatment and prevention. Central to these efforts is an understanding of the neutralizing antibody (nAb) response to SARS-CoV-2 and the determinants of that response. nAbs are of intense interest because their passive transfer protects against SARS-CoV-2 in various animal models [5–14], and their elicitation by vaccines correlates with protection in nonhuman primates [15]. Recently, an analysis of correlates of COVID-19 protection in the Phase 3 COVE Moderna mRNA-1273 vaccine trial confirmed preliminary analyses suggesting that nAbs correlate with vaccine efficacy in humans as well [16–18].

Materials and methods
From May through October 2020, 329 HIV-uninfected participants from the United States (n = 167) and Peru (n = 162) with a history of SARS-CoV-2 infection provided written informed consent and were enrolled into the HVTN 405/HPTN 1901 observational cohort study (NCT04403880) led by the COVID-19 Prevention Network (CoVPN). Participants were enrolled at 26 clinical research sites (CRS) in Peru and the US (S1 Text). Complete eligibility criteria are listed in S1 Text.

Participants were stratified by symptomatic and asymptomatic disease, inpatient or outpatient care requirement, and age (18 to 55 or >55 years of age). Asymptomatic individuals (n = 65, 19.8%) were eligible to enroll 2 to 10 weeks after the most recent test at which SARS-CoV-2 was detected; symptomatic individuals (n = 264, 80.2%) were eligible to enroll 1 to 8 weeks after resolution of COVID-19.

Overall, 54% of the cohort was Hispanic; 9% of the US cohort identified as Hispanic. About 52% of participants identified as Other race (98.8% of Peru participants and 6% of the US participants); 34% White (1.2% of Peru participants, 65.3% of the US participants); 11% Black (21.6% of the US participants), and 3.6% Asian (7.2% of the US participants) (Table 1). A greater proportion of participants from Peru than from the US had been hospitalized for COVID-19 (48.8% versus 31.7%); fewer participants from Peru were asymptomatic (17.3 versus 22.2%) (Table 1). SARS-CoV-2 testing was not available to asymptomatic individuals in Peru during the time of this study’s conduct; thus, most Peruvian participants who met the eligibility requirement of having had a prior test detecting SARS-CoV-2 also had a history of symptomatic infection.

An understanding of the role nAbs play in SARS-CoV-2 and COVID-19 may illuminate the path toward a post-pandemic future of protection by active and passive immunization and potentially by herd or community immunity, all of which are likely to depend heavily on nAbs. Moreover, knowing what factors influence nAb responses may inform improved treatments and better clinical outcomes. In our cohort of adults who had recently recovered from PCR-confirmed SARS-CoV-2 infection or COVID-19, being older, assigned male sex at birth, diabetic, having a BMI >30, and a history of more severe illness was associated with higher nAb titers and, except for sex, higher nAb response rates. Hypertension was associated with lower odds of a nAb response and lower titers.

Citation: Karuna S, Li SS, Grant S, Walsh SR, Frank I, Casapia M, et al. (2021) Neutralizing antibody responses over time in demographically and clinically diverse individuals recovered from SARS-CoV-2 infection in the United States and Peru: A cohort study. PLoS Med 18(12): e1003868.

Editor: James G. Beeson, Burnet Institute, AUSTRALIA

Received: May 20, 2021; Accepted: November 14, 2021; Published: December 6, 2021

Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Data Availability: The data underlying the findings of this manuscript can be found online at

Funding: This work was funded by NIAID/NIH UM1 AI069412 (SRW); NIAID/NIH 2UM1AI069534, NIAID/NIH UM1AI148452, NIAID/NIH 2P30-AI-045008 (IF); NIAID/NIH UM1 AI068614-14 (LC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have read the journal’s policy and the authors of this manuscript have the following competing interests: IF serves on advisory boards for Gilead and ViiV and receives grant money from Sanofi, Janssen and Moderna. SRW has received funding from NIH/NIAID as well as the Bill and Melinda Gates Foundation unrelated to this work; he has also conducted clinical trials funded by Janssen, Sanofi Pasteur, and Regeneron, also unrelated to this work. SK, LF, AKR, SG, LC, JGK, LP, MC, DM, OH, SSL, MT, MDM declare no conflicts of interest.

Abbreviations: ACE2, angiotensin-converting enzyme 2; ARB, angiotensin-receptor blocker; BMI, body mass index; CI, confidence interval; COVID-19, Coronavirus Disease 2019; CoVPN, COVID-19 Prevention Network; CRS, clinical research site; GAM, generalized additive model; GAMM, generalized additive mixed model; GMR, geometric mean ratio; GMT, geometric mean titer; IRB, Institutional Review Board; LOD, limit of detection; Luc, luciferase; mAb, monoclonal antibody; nAb, neutralizing antibody; NTD, N-terminal domain; OR, odds ratio; RBD, receptor binding domain; RLU, relative Luc unit; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2; yo, years old.

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