Fc mediated pan-sarbecovirus protection after alphavirus vector vaccination (preprint)

Two group 2B beta-coronaviruses (sarbecoviruses) have caused regional and global epidemics in modern history. The mechanisms of cross protection driven by the sarbecovirus spike, a dominant immunogen, are less clear yet critically important for pan-sarbecovirus vaccine development. We evaluated the mechanisms of cross-sarbecovirus protective immunity using a panel of alphavirus-vectored vaccines covering bat to human strains. While vaccination did not prevent virus replication, it protected against lethal heterologous disease outcomes in both SARS-CoV-2 and clade 2 bat sarbecovirus HKU3-SRBD challenge models. The spike vaccines tested primarily elicited a highly S1-specific homologous neutralizing antibody response with no detectable cross-virus neutralization. We found non-neutralizing antibody functions that mediated cross protection in wild-type mice were mechanistically linked to FcgR4 and spike S2-binding antibodies. Protection was lost in FcR knockout mice, further supporting a model for non-neutralizing, protective antibodies. These data highlight the importance of FcR-mediated cross-protective immune responses in universal pan-sarbecovirus vaccine designs.

Anamnestic Humoral Correlates of Immunity Across SARS-CoV-2 Variants of Concern (preprint)

While immune correlates against SARS-CoV-2 are typically defined at peak immunogenicity following vaccination, immunologic responses that expand selectively during the anamnestic response following infection can provide mechanistic and detailed insights into the immune mechanisms of protection. Moreover, whether anamnestic correlates are conserved across VoCs, including the Delta and more distant Omicron variant of concern (VoC), remains unclear. To define the anamnestic correlates of immunity, across VOCs, we deeply profiled the humoral immune response in individuals recently infected with either the Delta or Omicron VoC. While limited acute N-terminal domain and RBD-specific immune expansion was observed following breakthrough, a significant immunodominant expansion of opsinophagocytic Spike-specific antibody responses focused largely on the conserved S2-domain of SARS-CoV-2 was observed 1 week after breakthrough infection. This S2-specific functional humoral response continued to evolve over 2-3 weeks following both Delta and Omicron breakthrough infection, targeting multiple VoCs and common coronaviruses. These responses were focused largely on the fusion peptide 2 and heptad repeat 1, both associated with enhanced rates of viral clearance. Taken together, our results point to a critical role of highly conserved, functional S2-specific responses in the control of SARS-CoV-2 infection, across VOCs, and thus humoral response linked to virus attenuation can guide next-generation generation vaccine boosting approaches to confer broad protection against future SARS-CoV-2 VoCs.

mRNA vaccine boosting enhances antibody responses against SARS-CoV-2 Omicron variant in patients with antibody deficiency syndromes (preprint)

Patients with primary antibody deficiency syndromes (PAD) have poor humoral immune responses requiring immunoglobulin replacement therapy. We followed PAD patients after SARS-CoV-2 vaccination by evaluating their immunoglobulin replacement products and serum for anti-spike binding, Fc{gamma}R binding, and neutralizing activities. Immunoglobulin replacement products had low anti-spike and receptor binding domain (RBD) titers and neutralizing activity. In COVID-19-naive PAD patients, anti-spike and RBD titers increased after mRNA vaccination but decreased to pre-immunization levels by 90 days. Patients vaccinated after SARS-CoV-2 infection developed higher responses comparable to healthy donors. Most vaccinated PAD patients had serum neutralizing antibody titers above an estimated correlate of protection against ancestral SARS-CoV-2 and Delta virus but not against Omicron virus, although this was improved by boosting. Thus, currently used immunoglobulin replacement products likely have limited protective activity, and immunization and boosting of PAD patients with mRNA vaccines should confer at least short-term immunity against SARS-CoV-2 variants, including Omicron.