Whole virus-based inactivated SARS-CoV-2 vaccines adjuvanted with aluminum hydroxide have been critical to the COVID-19 pandemic response. Although these vaccines are protective against homologous coronavirus infection, the emergence of novel variants and the presence of large zoonotic reservoirs harboring novel heterologous coronaviruses provide significant opportunities for vaccine breakthrough, which raises the risk of adverse outcomes like vaccine-associated enhanced respiratory disease. Here, we use a female mouse model of coronavirus disease to evaluate inactivated vaccine performance against either homologous challenge with SARS-CoV-2 or heterologous challenge with a bat-derived coronavirus that represents a potential emerging disease threat. We show that inactivated SARS-CoV-2 vaccines adjuvanted with aluminum hydroxide can cause enhanced respiratory disease during heterologous infection, while use of an alternative adjuvant does not drive disease and promotes heterologous viral clearance. In this work, we highlight the impact of adjuvant selection on inactivated vaccine safety and efficacy against heterologous coronavirus infection.

The Ebola virus glycoprotein (GP) gene templates several mRNAs that produce either the virion-associated transmembrane protein or one of two secreted glycoproteins. Soluble glycoprotein (sGP) is the predominant product. GP1 and sGP share an amino terminal sequence of 295 amino acids but differ in quaternary structure, with GP1 being a heterohexamer with GP2 and sGP a homodimer. Two structurally different DNA aptamers were selected against sGP that also bound GP1,2. These DNA aptamers were compared with a 2′FY-RNA aptamer for their interactions with the Ebola GP gene products. The three aptamers have almost identical binding isotherms for sGP and GP1,2 in solution and on the virion. They demonstrated high affinity and selectivity for sGP and GP1,2. Furthermore, one aptamer, used as a sensing element in an electrochemical format, detected GP1,2 on pseudotyped virions and sGP with high sensitivity in the presence of serum, including from an Ebola-virus-infected monkey. Our results suggest that the aptamers interact with sGP across the interface between the monomers, which is different from the sites on the protein bound by most antibodies. The remarkable similarity in functional features of three structurally distinct aptamers suggests that aptamers, like antibodies, have preferred binding sites on proteins.

The COVID-19 pandemic led to the rapid and worldwide development of highly effective vaccines against SARS-CoV-2. However, there is significant individual-to-individual variation in vaccine efficacy due to factors including viral variants, host age, immune status, environmental and host genetic factors. Understanding those determinants driving this variation may inform the development of more broadly protective vaccine strategies. While host genetic factors are known to impact vaccine efficacy for respiratory pathogens such as influenza and tuberculosis, the impact of host genetic variation on vaccine efficacy against COVID-19 is not well understood. To model the impact of host genetic variation on SARS-CoV-2 vaccine efficacy, while controlling for the impact of non-genetic factors, we used the Diversity Outbred (DO) mouse model. We found that DO mice immunized against SARS-CoV-2 exhibited high levels of variation in vaccine-induced neutralizing antibody responses. While the majority of the vaccinated mice were protected from virus-induced disease, similar to human populations, we observed vaccine breakthrough in a subset of mice. Importantly, we found that this variation in neutralizing antibody, virus-induced disease, and viral titer is heritable, indicating that the DO serves as a useful model system for studying the contribution of genetic variation of both vaccines and disease outcomes.

Background: Outbreaks of zoonotic emerging infectious diseases, including viral hemorrhagic fevers, are increasing in frequency. Clinical detection remains challenging due to the lack of pathognomonic signs or symptoms and limited access to diagnostics. To better understand the prevalence of prior exposure to viral hemorrhagic fever viruses, serum from community participants in rural Liberia was tested for immunoglobulin G antibodies. Methods: Serum collected from individuals enrolled in the ENABLE study, an observational study of Lassa fever virus incidence and seroprevalence, were analyzed for immunoglobulin G against Ebola virus, Marburg virus, Lassa virus, Rift Valley Fever virus, Crimean-Congo hemorrhagic fever virus, pan-alphavirus, and pan-flavivirus by MAGPIX, a multiplex immune assay. Associations with seropositivity were evaluated using questionnaires that included demographic, animal, and environmental exposure information. Results: Eighty-eight percent of samples from 456 participants tested positive for ≥1 of the viral antibodies with a majority (63%) having antibodies to ≥2 viruses. Seropositivity was highest for Lassa virus (67%) followed by pan-flavivirus (51%), pan-alphavirus (35%), Crimean-Congo hemorrhagic fever virus (24%), Ebolavirus (13%), Rift Valley Fever virus (9%), and Marburg virus (8%). Older age, sex (variable by pathogen), and exposure to cats and rats were associated with seropositivity. Conclusions: These findings demonstrate a significant spillover of filoviruses, bunyaviruses, flaviviruses, and alphaviruses in rural Liberia in contrast with an absence of detected outbreaks. These data support the need for enhanced surveillance and understanding of the ecological and behavioral risk factors for zoonotic spillover events, across a spectrum of disease presentation, given their potential and ongoing threat to global public health.

Vaccines are a safe and highly effective tool for protecting both humans and animals against infectious diseases. Although vaccines currently in use in humans have robust safety records, historical examples show that some vaccines have resulted in adverse outcomes, including vaccine-associated enhanced respiratory disease (VAERD). VAERD occurs when preexisting vaccine-induced immunity worsens respiratory disease, rather than conferring protection during infection. Enhanced disease in the lower respiratory tract characteristic of VAERD includes worsened clinical manifestations such as pneumonia and bronchiolitis, as well as increased pulmonary pathology in vaccinated, infected individuals compared with their unvaccinated, infected counterparts. Mechanistically, VAERD has been associated with T_H2-mediated immunopathology or antibody-dependent enhancement and is primarily associated with specific virus families, including Pneumoviridae, Orthomyxoviridae and Coronaviridae. Notable cases of VAERD have been associated with a respiratory syncytial virus vaccine candidate evaluated in clinical trials in the 1960s, experimental coronavirus vaccines in animal models, and in veterinary vaccines for influenza virus in swine. Existing approved vaccines are safe and highly effective tools for protecting both humans and animals against respiratory pathogens. However, as new respiratory vaccines are developed, they must also undergo careful testing for VAERD or other adverse outcomes. This review aims to provide the field with an overview of VAERD as a resource to support vaccine development and safety studies.

Inactivated whole virus SARS-CoV-2 vaccines adjuvanted with aluminum hydroxide (Alum) are among the most widely used COVID-19 vaccines globally and have been critical to the COVID-19 pandemic response. Although these vaccines are protective against homologous virus infection in healthy recipients, the emergence of novel SARS-CoV-2 variants and the presence of large zoonotic reservoirs provide significant opportunities for vaccine breakthrough, which raises the risk of adverse outcomes including vaccine-associated enhanced respiratory disease (VAERD). To evaluate this possibility, we tested the performance of an inactivated SARS-CoV-2 vaccine (iCoV2) in combination with Alum against either homologous or heterologous coronavirus challenge in a mouse model of coronavirus-induced pulmonary disease. Consistent with human results, iCoV2 + Alum protected against homologous challenge. However, challenge with a heterologous SARS-related coronavirus, Rs-SHC014-CoV (SHC014), up to at least 10 months post-vaccination, resulted in VAERD in iCoV2 + Alum-vaccinated animals, characterized by pulmonary eosinophilic infiltrates, enhanced pulmonary pathology, delayed viral clearance, and decreased pulmonary function. In contrast, vaccination with iCoV2 in combination with an alternative adjuvant (RIBI) did not induce VAERD and promoted enhanced SHC014 clearance. Further characterization of iCoV2 + Alum-induced immunity suggested that CD4⁺ T cells were a major driver of VAERD, and these responses were partially reversed by re-boosting with recombinant Spike protein + RIBI adjuvant. These results highlight potential risks associated with vaccine breakthrough in recipients of Alum-adjuvanted inactivated vaccines and provide important insights into factors affecting both the safety and efficacy of coronavirus vaccines in the face of heterologous virus infections.