The vaccine-elicited immunoglobulin profile in milk after COVID-19 mRNA-based vaccination is IgG-dominant and lacks secretory antibodies

The Pfizer/BioNTech and Moderna mRNA-based COVID-19 vaccines are licensed under emergency use authorization, with millions of doses already administered globally [1]. No COVID-19 vaccines are yet under investigation for use in infants or young children. As such, the passive immunity of the antibodies (Abs) provided through milk from a vaccinated person may be one of the only ways to protect this population until pediatric COVID-19 vaccines are licensed. Our early work (as well as an expanded study being published concurrently with this report) examining the milk Ab response after SARS-CoV-2 infection demonstrated that Spike-specific IgA in milk after infection is dominant and highly correlated with a secretory Ab response [2]. Determining if secretory Abs are elicited in milk is critical, as this Ab class is highly stable and resistant to enzymatic degradation in all mucosae - not only in the infant oral/nasal cavity and gut, but in the airways and GI tract as well [3, 4]. Presently, we describe our analysis of the milk Ab response 14 days after completion of an mRNA-based COVID-19 vaccine regimen among 10 individuals. It was evident that unlike the post-infection milk Ab profile, IgG dominates after COVID-19 vaccination. One hundred percent of post-vaccine milk contained significant levels of Spike-specific IgG, with 8/10 samples exhibiting high IgG endpoint titers. Conversely, 6/10 (60%) of post-vaccine samples were positive for Spike specific IgA, with only 1 (10%) exhibiting high IgA endpoint titer. Furthermore, 5/10 (50%) post-vaccine milk samples contained Spike-specific secretory Ab, none of which were found to be high-titer. As our analyses of the immune response in milk to COVID-19 vaccination continues, it will provide a critical opportunity to address huge knowledge gaps, inform the field as to which COVID-19 vaccine, if any, is likely to provide the best milk Ab response, and highlight the need to design improved vaccines with protection of the breastfeeding infant in mind.

Human Milk Antibodies against S1 and S2 Subunits from SARS-CoV-2, HCoV-OC43, and HCoV-229E in Mothers with a Confirmed COVID-19 PCR, Viral SYMPTOMS, and Unexposed Mothers

Background: Preexisting immunity to SARS-CoV-2 could be related to cross-reactive antibodies to common human-coronaviruses (HCoVs). This study aimed to evaluate whether human milk antibodies against to S1 and S2 subunits SARS-CoV-2 are cross-reactive to S1 and S2 subunits HCoV-OC43 and HCoV-229E in mothers with a confirmed COVID-19 PCR test, in mothers with previous viral symptoms during COVID-19 pandemic, and in unexposed mothers; Methods: The levels of secretory IgA (SIgA)/IgA, secretory IgM (SIgM)/IgM, and IgG specific to S1 and S2 SARS-CoV-2, and reactive to S1 + S2 HCoV-OC43, and HCoV-229E were measured in milk from 7 mothers with a confirmed COVID-19 PCR test, 20 mothers with viral symptoms, and unexposed mothers (6 Ctl1-2018 and 16 Ctl2-2018) using ELISA; Results: The S2 SARS-CoV-2 IgG levels were higher in the COVID-19 PCR (p = 0.014) and viral symptom (p = 0.040) groups than in the Ctl1-2018 group. We detected a higher number of positive correlations between the antigens and secretory antibodies in the COVID-19 PCR group than in the viral symptom and Ctl-2018 groups. S1 + S2 HCoV-OC43-reactive IgG was higher in the COVID-19 group than in the control group (p = 0.002) but did not differ for the other antibodies; Conclusions: Mothers with a confirmed COVID-19 PCR and mothers with previous viral symptoms had preexisting human milk antibodies against S2 subunit SARS-CoV-2. Human milk IgG were more specific to S2 subunit SARS-CoV-2 than other antibodies, whereas SIgA and SIgM were polyreactive and cross-reactive to S1 or S2 subunit SARS-CoV-2.

Enhanced SARS-CoV-2 neutralization by dimeric IgA

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), primarily infects cells at mucosal surfaces. Serum neutralizing antibody responses are variable and generally low in individuals that suffer mild forms of COVID-19. Although potent IgG antibodies can neutralize the virus, less is known about secretory antibodies such as IgA that might impact the initial viral spread and transmissibility from the mucosa. Here we characterize the IgA response to SARS-CoV-2 in a cohort of 149 convalescent individuals following diagnosis with COVID-19. IgA responses in plasma generally correlated with IgG responses. Further, clones of IgM-, IgG-, and IgA-producing B cells were derived from common progenitor cells. Plasma IgA monomers specific to SARS-CoV-2 proteins were demonstrated to be two-fold less potent than IgG equivalents. However, IgA dimers, the primary form of antibody in the nasopharynx, were on average fifteen times more potent than IgA monomers against the same target. Thus, dimeric IgA responses may be particularly valuable for protection against SARS-CoV-2 and for vaccine efficacy.

Enhanced SARS-CoV-2 Neutralization by Secretory IgA in vitro

SARS-CoV-2 primarily infects cells at mucosal surfaces. Serum neutralizing antibody responses are variable and generally low in individuals that suffer mild forms of the illness. Although potent IgG antibodies can neutralize the virus, less is known about secretory antibodies such as IgA that might impact the initial viral spread and transmissibility from the mucosa. Here we characterize the IgA response to SARS-CoV-2 in a cohort of 149 individuals. IgA responses in plasma generally correlate with IgG responses and clones of IgM, IgG and IgA producing B cells that are derived from common progenitors are evident. Plasma IgA monomers are 2-fold less potent than IgG equivalents. However, IgA dimers, the primary form in the nasopharynx, are on average 15 times more potent than IgA monomers. Thus, secretory IgA responses may be particularly valuable for protection against SARS-CoV-2 and for vaccine efficacy.