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Summary: The rapid emergence of SARS-CoV-2 variants of concern (VoC) and the threat of future zoonotic sarbecovirus spillover emphasizes the need for broadly protective next-generation vaccines and therapeutics. We utilized SARS-CoV-2 spike ferritin nanoparticle (SpFN), and SARS-CoV-2 receptor binding domain ferritin nanoparticle (RFN) immunogens, in an equine model to elicit hyperimmune sera and evaluated its sarbecovirus neutralization and protection capacity. Immunized animals rapidly elicited sera with the potent neutralization of SARS-CoV-2 VoC, and SARS-CoV-1 pseudoviruses, and potent binding against receptor binding domains from sarbecovirus clades 1b, 1a, 2, 3, and 4. Purified equine polyclonal IgG provided protection against Omicron XBB.1.5 virus in the K18-hACE2 transgenic mouse model. These results suggest that SARS-CoV-2-based nanoparticle vaccines can rapidly produce a broad and protective sarbecovirus response in the equine model and that equine serum has therapeutic potential against emerging SARS-CoV-2 VoC and diverse sarbecoviruses, presenting a possible alternative or supplement to monoclonal antibody immunotherapies.

Abstract This study demonstrates the impact of adjuvant on the development of T follicular helper (Tfh) and B cells, and their influence on antibody responses in mice vaccinated with SARS-CoV-2-spike-ferritin-nanoparticle (SpFN) adjuvanted with either Army Liposome Formulation containing QS-21 (SpFN + ALFQ) or Alhydrogel® (SpFN + AH). SpFN + ALFQ increased the size and frequency of germinal center (GC) B cells in the vaccine-draining lymph nodes and increased the frequency of antigen-specific naive B cells. A single vaccination with SpFN + ALFQ resulted in a higher frequency of IL-21-producing-spike-specific Tfh and GC B cells in the draining lymph nodes and spleen, S-2P protein-specific IgM and IgG antibodies, and elicitation of robust cross-neutralizing antibodies against SARS-CoV-2 variants as early as day 7, which was enhanced by a second vaccination. This was associated with the generation of high titer, high avidity binding antibodies. The third vaccination with SpFN + ALFQ elicited high levels of neutralizing antibodies against the Omicron variant. No cross-neutralizing antibodies against Omicron were induced with SpFN + AH. These findings highlight the importance of ALFQ in orchestrating early induction of antigen-specific Tfh and GC B cell responses and long-lived plasma cells in the bone marrow. The early engagement of S-2P specific naive B cells and high titer IgM antibodies shape the development of long-term neutralization breadth.

SARS-CoV-2 variants of concern continue to emerge, reducing vaccine efficacy and limiting therapeutic options. Here, Chen and colleagues describe the identification and design of shark nanobodies with pansarbecovirus activity.

IntroductionAs the SARS-CoV-2 pandemic continues to evolve, we face new variants of concern with a concurrent decline in vaccine booster uptake. We aimed to evaluate the difference in immunity gained from the original SARS-CoV-2 mRNA vaccine series in pregnancy versus SARS-CoV-2 exposure during pregnancy against recent variants of concern.Study DesignThis is a retrospective analysis of previously collected samples from 192 patients who delivered between February 2021 and August 2021. Participants were categorized as 1) COVID vaccine: mRNA vaccine in pregnancy, 2) COVID-exposed, and 3) controls. The primary outcome was neutralizing capacity against wild-type, Delta, and Omicron-B1 between cohorts. Secondary outcomes include a comparison of cord-blood ID50 as well as the efficiency of vertical transfer, measured by cord-blood:maternal blood ID50 for each variant.ResultsPregnant women with COVID-19 vaccination had a greater spike in IgG titers compared to both those with COVID-19 disease exposure and controls. Both COVID exposure and vaccination resulted in immunity against Delta, but only COVID vaccination resulted in significantly greater Omicron ID-50 versus controls. The neutralizing capacity of serum from newborns was lower than that of their mothers, with COVID-vaccination demonstrating higher cord-blood ID50 vs wildtype and Delta variants compared to control or COVID-exposed, but neither COVID-exposure nor vaccination demonstrated significantly higher Omicron ID50 in cord-blood compared to controls. There was a 0.20 (0.07-0.33, p=0.004) and 0.12 (0.0-0.24, p=0.05) increase in cord-blood:maternal blood ID50 with COVID vaccination compared to COVID-19 exposure for wild-type and Delta respectively. In pair-wise comparison, vertical transfer of neutralization capacity (cord-blood:maternal blood ID50) was greatest for wild-type and progressively reduced for Delta and Omicron ID50.ConclusionPregnant patients with either an initial mRNA vaccination series or COVID-exposure demonstrated reduced immunity against newer variants compared to wild-type as has been reported for non-pregnant individuals; however, the COVID-vaccination series afforded greater cross-variant immunity to pregnant women, specifically against Omicron, than COVID-disease. Vertical transfer of immunity is greater in those with COVID vaccination vs COVID disease exposure but is reduced with progressive variants. Our results reinforce the importance of bivalent booster vaccination in pregnancy for both maternal and infant protection and also provide a rationale for receiving updated vaccines as they become available.

Summary: Background: COVID-19 vaccines have been critical for protection against severe disease following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) but gaps remain in our understanding of the immune responses that contribute to controlling subclinical and mild infections. Methods: Vaccinated, active-duty US military service members were enrolled in a non-interventional, minimal-risk, observational study starting in May, 2021. Clinical data, serum, and saliva samples were collected from study participants and were used to characterise the humoral immune responses to vaccination and to assess its impact on clinical and subclinical infections, as well as virologic outcomes of breakthrough infections (BTI) including viral load and infection duration. Findings: The majority of VIRAMP participants had received the Pfizer COVID-19 vaccine and by January, 2022, N = 149 had a BTI. The median BTI duration (PCR+ days) was 4 days and the interquartile range was 1–8 days. Participants that were nucleocapsid seropositive prior to their BTI had significantly higher levels of binding and functional antibodies to the spike protein, shorter median duration of infections, and lower median peak viral loads compared to seronegative participants. Furthermore, levels of neutralising antibody, ACE2 blocking activity, and spike-specific IgA measured prior to BTI also correlated with the duration of infection. Interpretation: We extended previous findings and demonstrate that a subset of vaccine-induced humoral immune responses, along with nucleocapsid serostatus are associated with control of SARS-CoV-2 breakthrough infections in the upper airways. Funding: This work was funded by the DoD Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense (JPEO-CBRND) in collaboration with the Defense Health Agency (DHA) COVID-19 funding initiative for the VIRAMP study.

Prior immune responses to coronaviruses might affect human SARS-CoV-2 response. We screened 2,565 serum and plasma samples collected from 2013 through early 2020, before the COVID-19 pandemic began, from 2,250 persons in 4 countries in Africa (Kenya, Nigeria, Tanzania, and Uganda) and in Thailand, including persons living with HIV-1. We detected IgG responses to SARS-CoV-2 spike (S) subunit 2 protein in 1.8% of participants. Profiling against 23 coronavirus antigens revealed that responses to S, subunit 2, or subunit 1 proteins were significantly more frequent than responses to the receptor-binding domain, S-Trimer, or nucleocapsid proteins (p

The emergence of novel potentially pandemic pathogens necessitates the rapid manufacture and deployment of effective, stable, and locally manufacturable vaccines on a global scale. In this study, the ability of the Escherichia coli expression system to produce the receptor binding domain (RBD) of the SARS-CoV-2 spike protein was evaluated. The RBD of the original Wuhan-Hu1 variant and of the Alpha and Beta variants of concern (VoC) were expressed in E. coli, and their biochemical and immunological profiles were compared to RBD produced in mammalian cells. The E. coli-produced RBD variants recapitulated the structural character of mammalian-expressed RBD and bound to human angiotensin converting enzyme (ACE2) receptor and a panel of neutralizing SARS-CoV-2 monoclonal antibodies. A pilot vaccination in mice with bacterial RBDs formulated with a novel liposomal adjuvant, Army Liposomal Formulation containing QS21 (ALFQ), induced polyclonal antibodies that inhibited RBD association to ACE2 in vitro and potently neutralized homologous and heterologous SARS-CoV-2 pseudoviruses. Although all vaccines induced neutralization of the non-vaccine Delta variant, only the Beta RBD vaccine produced in E. coli and mammalian cells effectively neutralized the Omicron BA.1 pseudovirus. These outcomes warrant further exploration of E. coli as an expression platform for non-glycosylated, soluble immunogens for future rapid response to emerging pandemic pathogens.

The COVID-19 pandemic has had a staggering impact on social, economic, and public health systems worldwide. Vaccine development and mobilization against SARS-CoV-2 (the etiologic agent of COVID-19) has been rapid. However, novel strategies are still necessary to slow the pandemic, and this includes new approaches to vaccine development and/or delivery that will improve vaccination compliance and demonstrate efficacy against emerging variants. Here, we report on the immunogenicity and efficacy of a SARS-CoV-2 vaccine comprising stabilized, pre-fusion spike protein trimers displayed on a ferritin nanoparticle (SpFN) adjuvanted with either conventional aluminum hydroxide or the Army Liposomal Formulation QS-21 (ALFQ) in a cynomolgus macaque COVID-19 model. Vaccination resulted in robust cell-mediated and humoral responses and a significant reduction in lung lesions following SARS-CoV-2 infection. The strength of the immune response suggests that dose sparing through reduced or single dosing in primates may be possible with this vaccine. Overall, the data support further evaluation of SpFN as a SARS-CoV-2 protein-based vaccine candidate with attention to fractional dosing and schedule optimization.