Evolution of Antibody Immunity to SARS-CoV-2

Abstract

SARS-CoV-2 has infected 47 million individuals and is responsible for over 1.2 million deaths to date. Infection is associated with development of variable levels of antibodies with neutralizing activity that can protect against infection in animal models. Antibody levels decrease with time, but the nature and quality of the memory B cells that would be called upon to produce antibodies upon re-infection has not been examined. Here we report on the humoral memory response in a cohort of 87 individuals assessed at 1.3 and 6.2 months after infection. We find that IgM, and IgG anti-SARS-CoV-2 spike protein receptor binding domain (RBD) antibody titers decrease significantly with IgA being less affected. Concurrently, neutralizing activity in plasma decreases by five-fold in pseudotype virus assays. In contrast, the number of RBD-specific memory B cells is unchanged. Memory B cells display clonal turnover after 6.2 months, and the antibodies they express have greater somatic hypermutation, increased potency and resistance to RBD mutations, indicative of continued evolution of the humoral response. Analysis of intestinal biopsies obtained from asymptomatic individuals 3 months after COVID-19 onset, using immunofluorescence, electron tomography or polymerase chain reaction, revealed persistence of SARS-CoV-2 in the small bowel of 7 out of 14 volunteers. We conclude that the memory B cell response to SARS-CoV-2 evolves between 1.3 and 6.2 months after infection in a manner that is consistent with antigen persistence.

Stable neutralizing antibody levels six months after mild and severe COVID-19 episode

“…However, our findings support the hypothesis of Gaebler et al, who suggested that the accumulation of IgG somatic mutations-and subsequent production of antibodies with increased neutralizing potency-allow the maintenance of neutralizing activity levels, despite the decline in specific antibody titers 5 . Of note, our follow-up period encompassed two waves of the COVID-19 outbreak in our country.…”

“…For the latter analysis, linear mixed-effect models with random intercepts and slopes were used, and different breakpoints were tested; the one with the best adjustment was chosen. For the longitudinal analysis of neutralizing activity, patients were grouped into two severity groups according to the WHO progression scale as proposed elsewhere 21 : asymptomatic or mild (levels 1-3), and hospitalized (levels [4][5][6][7][8][9][10]. Differences between the two severity groups were assessed using the likelihood ratio Figure 1a; Mann-Whitney test for comparative analysis) and modeled data as dotted lines (likelihood ratio test for comparative analysis).…”

Model-based evaluation of the impact of noncompliance with public health measures on COVID-19 disease control

“…The model's initial conditions are set to approximate current US disease prevalence and seroprevalence (as of November 2020): ( = 0) = 0.2 % ( = 0) = 8% (34) Our model lacks a seasonal component for SARS-CoV-2 transmission, as such associations have been conjectured (35) but not proven, and it also assumes a 18-month duration of natural immunity, as an optimistic estimate based on the duration of antibody responses seen so far months (20)(21)(22). The disease-preventing interventions and return to normalcy (which would correspond to a return to the pre-pandemic R0 of 5.7) are assumed to occur at the beginning of the simulation interval.…”

“…If immunity to SARS-CoV-2 by natural infection is not life-long, as suggested by many studies (20)(21)(22), and if effective interventions are not undertaken at a large scale, the virus will become endemic. As shown in Figure 4, this means that in the long term, SARS-CoV-2 will reach a steady-state prevalence in the population.…”

“…The high reproductive number (R0) of SARS-CoV-2 (reported to be 5.7 in the early days of the pandemic in Wuhan (17)) creates the potential for explosive growth in situations where the virus has not been completely eradicated, as has been demonstrated by a massive second wave in many European countries (18,19). Making matters worse, estimates for natural immunity as a consequence of SARS-CoV-2 infection range from six to twenty-four months (20)(21)(22), creating the potential for multiple waves of disease in the short term.…”