Although SARS-CoV-2 infects the upper respiratory tract, we know little about the amount, type, and kinetics of antibodies (Ab) generated in the oral cavity in response to COVID-19 vaccination. We collected serum and saliva samples from participants receiving two doses of mRNA COVID-19 vaccines and measured the level of anti-SARS-CoV-2 Ab. We detected anti-Spike and anti-Receptor Binding Domain (RBD) IgG and IgA, as well as anti-Spike/RBD associated secretory component in the saliva of most participants after dose 1. Administration of a second dose of mRNA boosted the IgG but not the IgA response, with only 30% of participants remaining positive for IgA at this timepoint. At 6 months post-dose 2, these participants exhibited diminished anti-Spike/RBD IgG levels, although secretory component-associated anti-Spike Ab were more stable. Examining two prospective cohorts we found that participants who experienced breakthrough infections with SARS-CoV-2 variants had lower levels of vaccine-induced serum anti-Spike/RBD IgA at 2–4 weeks post-dose 2 compared to participants who did not experience an infection, whereas IgG levels were comparable between groups. These data suggest that COVID-19 vaccines that elicit a durable IgA response may have utility in preventing infection.
Vaccination induced antibody and T-cell immune responses are important for systemic protection from COVID-19. Because SARS-CoV-2 infects and is transmitted by oral-pharyngeal mucosa, we wished to test mucosal antibodies elicited by natural infection or intramuscular vaccine injection. In a non-randomized observational study, we measured antibodies against the SARS-CoV-2 RBD in plasma and saliva from convalescent or vaccinated individuals and tested their neutralizing potential using a replication competent rVSV-eGFP-SARS-CoV-2. We found IgG and IgA anti-RBD antibodies as well as neutralizing activity in convalescent plasma and saliva. Two doses of mRNA vaccination (BNT162b2 or mRNA-1273) induced high levels of IgG anti-RBD in saliva, a subset of whom also had IgA, and significant neutralizing activity. We detected anti-RBD IgG and IgA with significant neutralizing potential in the plasma of single dose Ad26.COV2.S vaccinated individuals, and we detected slight amounts of anti-RBD antibodies in matched saliva. The role of salivary antibodies in protection against SARS-CoV-2 infection is unknown and merits further investigation. This study was not designed to, nor did it study the full kinetics of the antibody response or protection from infection, nor did it address variants of SARS-CoV-2.
Vaccines against SARS-CoV-2 administered via the parenteral route (intra-muscular = i.m.) are effective at preventing COVID-19 in part by inducing neutralizing antibodies in the blood. The first line of defense against SARS-CoV-2 is in the upper respiratory tract, yet we know very little about whether COVID-19 vaccines induce immunity in this compartment, if at all. We analysed salivary antibodies against the SARS-CoV-2 Spike protein and its receptor binding domain (RBD) following 2 i.m. injections of either BNT162b2 or mRNA-1273 vaccines. Salivary anti-Spike/RBD IgG was detected after 1 dose and increased further after dose 2, reflecting the systemic immune response. Interestingly, salivary anti-Spike/RBD IgA associated with the secretory component (sIgA) was detected in nearly all vaccinated participants after one dose of mRNA vaccine, with anti-Spike sIgA diminishing after dose 2. Vaccination with ChAdOx1-S (Ad) followed by mRNA induced similar levels of salivary anti-Spike/RBD IgG and IgA, and both mRNA/mRNA and Ad/mRNA regimes provoked modest neutralizing capacity in this biofluid. Our results demonstrate that SARS-CoV-2 mRNA/mRNA and Ad/mRNA vaccination induces antibodies in the saliva, and in response to one dose of mRNA, a compartmentalized and transient antigen-specific sIgA response is generated that does not correlate with systemic immunity.
Lyme disease, caused by the bacteria Borrelia burgdorferi, is the most common and rapidly growing vector-borne infectious disease in the United States and Europe. High variability in disease burden among Lyme patients suggests that individual immune responses may be key drivers of clinical presentation and patient outcomes. Use of high resolution flow-based immunosorbent profiling revealed that a subset of Lyme patients with persistent symptoms were producing high concentrations of IgE specific to B. burgdorferi. Comparing C57B/6 mice, which are tolerant to B. burgdorferi, and C3H/HeJ mice, which are susceptible to disease, we find high levels of IgE specific for B. burgdorferi in C3H/HeJ but not C57B/6 mice. Furthermore, IgE was found to target Borrelia peptidoglycan in both acute and chronic infection models. Histologic analysis of mouse Lyme arthritic ankle tissue showed mast cells, which release highly immunogenic effectors upon activation by bound IgE, degranulating at significantly higher rates compared to uninfected controls. Forced mast cell degranulation exacerbated Lyme arthritis in infected mice. This data suggests that a subset of Lyme patients with persistent symptoms may have developed an allergic response to conserved bacterial antigens from a B. burgdorferi infection, as opposed to an autoimmune type response. Inclusion of IgE reactivity in diagnostic testing and examination of pathological immune responses to bacterial antigens could assist clinicians in patient care and effective treatments. Research reported in this publication was supported by the Fairbairn family foundation; Bay Area Lyme Foundation; the Younger family foundation; the Robert J. Kleberg, Jr., and Helen C. Kleberg Foundation; the Virginia and D. K. Ludwig Fund for Cancer Research; M.C.T. was supported by Stanford Immunology training grant 5T32AI007290, and the NIH NRSA 1 F32 AI124558-01 award. L.B.T.D. was supported by a Stanford Diversifying Academia Recruiting Excellence fellowship. S.D.G was supported by the California Institute for Regenerative Medicine Bridges 2.0 Training Program grant EDUC2-08397. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Neutralizing activity found in the blood following intramuscular vaccination protects against systemic disease from SARS-CoV-2 infection. Mild breakthrough mucosal infections in vaccinated individuals can contribute to transmission chains of infection, and as such the contribution of intramuscular vaccination to mucosal immunity is important to understand. We assessed vesicular stomatitis virus (VSV) SARS-CoV-2 SPIKE protein neutralization activities as well as anti-viral spike and RBD IgG and IgA isotype antibody binding, in saliva from individuals who had recovered from SARS-CoV-2 infection and people who received immunization. The various vaccination strategies deployed globally showed key differences in the extent of neutralizing activity that could be measured. Even in subjects with significant peak activity 2–4 weeks following a second dose of mRNA vaccination, this neutralizing activity was transient and significantly reduced within 3–6 months. Among adenoviral vectors, ChAdOx1 elicited significantly more salivary neutralizing activity and antibody levels compared to Ad26.S. A large range of salivary neutralizing activity is induced following different intramuscular SARS-COV-2 vaccination strategies. All were orders of magnitude lower than neutralization levels observed in blood, and it remains to be determined if any of the observed neutralizing activity in the saliva can neutralize virus in the upper respiratory tract upon exposure. Based on studies where high levels of mucosal IgA antibodies were induced in response to stimulation with aerosol intranasal vaccines, such vaccines could be important in lowering transmission of SARS-COV-2. Supported by The Fairbairn Foundation and SPARK
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