Fc-γR-dependent antibody effector functions are required for vaccine-mediated protection against antigen-shifted variants of SARS-CoV-2.

Emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with antigenic changes in the spike protein are neutralized less efficiently by serum antibodies elicited by legacy vaccines against the ancestral Wuhan-1 virus. Nonetheless, these vaccines, including mRNA-1273 and BNT162b2, retained their ability to protect against severe disease and death, suggesting that other aspects of immunity control infection in the lung. Vaccine-elicited antibodies can bind Fc gamma receptors (FcγRs) and mediate effector functions against SARS-CoV-2 variants, and this property correlates with improved clinical coronavirus disease 2019 outcome. However, a causal relationship between Fc effector functions and vaccine-mediated protection against infection has not been established. Here, using passive and active immunization approaches in wild-type and FcγR-knockout mice, we determined the requirement for Fc effector functions to control SARS-CoV-2 infection. The antiviral activity of passively transferred immune serum was lost against multiple SARS-CoV-2 strains in mice lacking expression of activating FcγRs, especially murine FcγR III (CD16), or depleted of alveolar macrophages. After immunization with the pre-clinical mRNA-1273 vaccine, control of Omicron BA.5 infection in the respiratory tract also was lost in mice lacking FcγR III. Our passive and active immunization studies in mice suggest that Fc-FcγR engagement and alveolar macrophages are required for vaccine-induced antibody-mediated protection against infection by antigenically changed SARS-CoV-2 variants, including Omicron strains.

Infant rhesus macaques immunized against SARS-CoV-2 are protected against heterologous virus challenge one year later.

The U.S. Food and Drug Administration only gave emergency-use-authorization of the BNT162b2 and the mRNA-1273 SARS-CoV-2 vaccines for infants 6 months and older in June 2022. Yet, questions regarding the durability of vaccine efficacy, especially against emerging variants, in this age group remain. We demonstrated previously that a two-dose regimen of stabilized prefusion Washington SARS-CoV-2 S-2P spike (S) protein encoded by mRNA encapsulated in lipid nanoparticles (mRNA-LNP) or purified S-2P mixed with 3 M-052, a synthetic toll-like receptor (TLR) 7/8 agonist, in a squalene emulsion (Protein+3 M-052-SE) was safe and immunogenic in infant rhesus macaques. Here, we demonstrate that broadly neutralizing and spike-binding antibodies against variants of concern (VOC), as well as T cell responses, persisted for 12 months. At one year, corresponding to human toddler age, we challenged vaccinated rhesus macaques and age-matched non-vaccinated controls intranasally and intratracheally with a high-dose of heterologous SARS-CoV-2 B.1.617.2 (Delta). Seven of eight control rhesus macaques exhibited severe interstitial pneumonia and high virus replication in the upper and lower respiratory tract. In contrast, vaccinated rhesus macaques had faster viral clearance with mild to no pneumonia. Neutralizing and binding antibody responses to the B.1.617.2 variant at the day of challenge correlated with lung pathology and reduced virus replication. Overall, the Protein+3 M-052-SE vaccine provided superior protection to the mRNA-LNP vaccine, emphasizing opportunities for optimization of current vaccine platforms. Notably, the observed efficacy of both vaccines one year after vaccination supports the implementation of an early life SARS-CoV-2 vaccine.

Bivalent SARS-CoV-2 mRNA vaccines increase breadth of neutralization and protect against the BA.5 Omicron variant in mice.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants in the Omicron lineage has resulted in diminished Coronavirus Disease 2019 (COVID-19) vaccine efficacy and persistent transmission. In this study, we evaluated the immunogenicity and protective efficacy of two, recently authorized, bivalent COVID-19 vaccines that contain two mRNAs encoding Wuhan-1 and either BA.1 (mRNA-1273.214) or BA.4/5 (mRNA-1273.222) spike proteins. As a primary two-dose immunization series in mice, both bivalent vaccines induced greater neutralizing antibody responses against Omicron variants than the parental, monovalent mRNA-1273 vaccine. When administered to mice as a booster at 7 months after the primary vaccination series with mRNA-1273, the bivalent vaccines induced broadly neutralizing antibody responses. Whereas most anti-Omicron receptor binding domain antibodies in serum induced by mRNA-1273, mRNA-1273.214 and mRNA-1273.222 boosters cross-reacted with the antecedent Wuhan-1 spike antigen, the mRNA-1273.214 and mRNA-1273.222 bivalent vaccine boosters also induced unique BA.1-specific and BA.4/5-specific responses, respectively. Although boosting with parental or bivalent mRNA vaccines substantially improved protection against BA.5 compared to mice receiving two vaccine doses, the levels of infection, inflammation and pathology in the lung were lowest in animals administered the bivalent mRNA vaccines. Thus, boosting with bivalent Omicron-based mRNA-1273.214 or mRNA-1273.222 vaccines enhances immunogenicity and confers protection in mice against a currently circulating SARS-CoV-2 strain.

Safety, immunogenicity and antibody persistence of a bivalent Beta-containing booster vaccine against COVID-19: a phase 2/3 trial.

Updated immunization strategies are needed to address multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Here we report interim results from an ongoing, open-label phase 2/3 trial evaluating the safety and immunogenicity of the bivalent Coronavirus Disease 2019 (COVID-19) vaccine candidate mRNA-1273.211, which contains equal mRNA amounts encoding the ancestral SARS-CoV-2 and Beta variant spike proteins, as 50-µg (n = 300) and 100-µg (n = 595) first booster doses administered approximately 8.7-9.7 months after the mRNA-1273 primary vaccine series ( NCT04927065 ). The primary objectives were to evaluate the safety and reactogenicity of mRNA-1273.211 and to demonstrate non-inferior antibody responses compared to the mRNA-1273 100-µg primary series. Additionally, a pre-specified immunogenicity objective was to demonstrate superior antibody responses compared to the previously authorized mRNA-1273 50-µg booster. The mRNA-1273.211 booster doses (50-µg or 100-µg) 28 days after immunization elicited higher neutralizing antibody responses against the ancestral SARS-CoV-2 and Beta variant than those elicited 28 days after the second mRNA­1273 dose of the primary series ( NCT04470427 ). Antibody responses 28 days and 180 days after the 50-µg mRNA-1273.211 booster dose were also higher than those after a 50-µg mRNA-1273 booster dose ( NCT04405076 ) against the ancestral SARS-CoV-2 and Beta, Omicron BA.1 and Delta variants, and all pre-specified immunogenicity objectives were met. The safety and reactogenicity profile of the bivalent mRNA-1273.211 booster (50-µg) was similar to the booster dose of mRNA-1273 (50-µg). Immunization with the primary series does not set a ceiling to the neutralizing antibody response, and a booster dose of the bivalent vaccine elicits a robust response with titers that are likely to be protective against COVID-19. These results indicate that bivalent booster vaccines can induce potent, durable and broad antibody responses against multiple variants, providing a new tool in response to emerging variants.

A Bivalent Omicron-Containing Booster Vaccine against Covid-19.

BACKGROUND: The safety and immunogenicity of the bivalent omicron-containing mRNA-1273.214 booster vaccine are not known. METHODS: In this ongoing, phase 2-3 study, we compared the 50-µg bivalent vaccine mRNA-1273.214 (25 µg each of ancestral Wuhan-Hu-1 and omicron B.1.1.529 [BA.1] spike messenger RNAs) with the previously authorized 50-µg mRNA-1273 booster. We administered mRNA-1273.214 or mRNA-1273 as a second booster in adults who had previously received a two-dose (100-µg) primary series and first booster (50-µg) dose of mRNA-1273 (≥3 months earlier). The primary objectives were to assess the safety, reactogenicity, and immunogenicity of mRNA-1273.214 at 28 days after the booster dose. RESULTS: Interim results are presented. Sequential groups of participants received 50 µg of mRNA-1273.214 (437 participants) or mRNA-1273 (377 participants) as a second booster dose. The median time between the first and second boosters was similar for mRNA-1273.214 (136 days) and mRNA-1273 (134 days). In participants with no previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the geometric mean titers of neutralizing antibodies against the omicron BA.1 variant were 2372.4 (95% confidence interval [CI], 2070.6 to 2718.2) after receipt of the mRNA-1273.214 booster and 1473.5 (95% CI, 1270.8 to 1708.4) after receipt of the mRNA-1273 booster. In addition, 50-µg mRNA-1273.214 and 50-µg mRNA-1273 elicited geometric mean titers of 727.4 (95% CI, 632.8 to 836.1) and 492.1 (95% CI, 431.1 to 561.9), respectively, against omicron BA.4 and BA.5 (BA.4/5), and the mRNA-1273.214 booster also elicited higher binding antibody responses against multiple other variants (alpha, beta, gamma, and delta) than the mRNA-1273 booster. Safety and reactogenicity were similar with the two booster vaccines. Vaccine effectiveness was not assessed in this study; in an exploratory analysis, SARS-CoV-2 infection occurred in 11 participants after the mRNA-1273.214 booster and in 9 participants after the mRNA-1273 booster. CONCLUSIONS: The bivalent omicron-containing vaccine mRNA-1273.214 elicited neutralizing antibody responses against omicron that were superior to those with mRNA-1273, without evident safety concerns. (Funded by Moderna; ClinicalTrials.gov number, NCT04927065.).

Distinct sensitivities to SARS-CoV-2 variants in vaccinated humans and mice.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019 has led to the development of a large number of vaccines, several of which are now approved for use in humans. Understanding vaccine-elicited antibody responses against emerging SARS-CoV-2 variants of concern (VOCs) in real time is key to inform public health policies. Serum neutralizing antibody titers are the current best correlate of protection from SARS-CoV-2 challenge in non-human primates and a key metric to understand immune evasion of VOCs. We report that vaccinated BALB/c mice do not recapitulate faithfully the breadth and potency of neutralizing antibody responses elicited by various vaccine platforms against VOCs, compared with non-human primates or humans, suggesting caution should be exercised when interpreting data obtained with this animal model.

Messenger ribonucleic acid vaccines against infectious diseases: current concepts and future prospects.

Over the past two decades, scientific and technological advancements have revealed messenger ribonucleic acid (mRNA)-based vaccines as a well-tolerated and effective platform to combat infectious disease. The potential of mRNA-based vaccines was epitomized during the severe acute respiratory syndrome coronavirus 2 pandemic, wherein mRNA-based vaccines were rapidly developed and found highly efficacious with an acceptable safety profile. These properties together with the capability to quickly address pathogens of pandemic potential, pathogens with complex antigens, and multiple pathogens within a single vaccine have revitalized the field, and multiple mRNA-based vaccines have now entered clinical development. This review summarizes current mRNA-based vaccine technology, perspectives on ongoing clinical studies, and future prospects for the field.

mRNA-1273 and Ad26.COV2.S vaccines protect against the B.1.621 variant of SARS-CoV-2.

BACKGROUND: Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019, viral variants with greater transmissibility or immune-evasion properties have arisen, which could jeopardize recently deployed vaccine- and antibody-based countermeasures. METHODS: Here, we evaluated in mice and hamsters the efficacy of a pre-clinical version of the Moderna mRNA vaccine (mRNA-1273) and the Johnson & Johnson recombinant adenoviral-vectored vaccine (Ad26.COV2.S) against the B.1.621 (Mu) variant of SARS-CoV-2, which contains spike mutations T95I, Y144S, Y145N, R346K, E484K, N501Y, D614G, P681H, and D950N. FINDINGS: Immunization of 129S2 and K18-human ACE2 transgenic mice with the mRNA-1273 vaccine protected against weight loss, lung infection, and lung pathology after challenge with the B.1.621 or WA1/2020 N501Y/D614G SARS-CoV-2 strain. Similarly, immunization of 129S2 mice and Syrian hamsters with a high dose of Ad26.COV2.S reduced lung infection after B.1.621 virus challenge. CONCLUSIONS: Thus, immunity induced by the mRNA-1273 or Ad26.COV2.S vaccine can protect against the B.1.621 variant of SARS-CoV-2 in multiple animal models. FUNDING: This study was supported by the NIH (R01 AI157155 and U01 AI151810), NIAID Centers of Excellence for Influenza Research and Response [CEIRR] contracts 75N93021C00014 and 75N93021C00016, and the Collaborative Influenza Vaccine Innovation Centers [CIVIC] contract 75N93019C00051. It was also supported, in part, by the National Institutes of Allergy and Infectious Diseases Center for Research on Influenza Pathogenesis (HHSN272201400008C) and the Japan Program for Infectious Diseases Research and Infrastructure (JP21wm0125002) from the Japan Agency for Medical Research and Development (AMED).

Boosting with variant-matched or historical mRNA vaccines protects against Omicron infection in mice.

The large number of spike substitutions in Omicron lineage variants (BA.1, BA.1.1., and BA.2) could jeopardize the efficacy of SARS-CoV-2 vaccines. We evaluated in mice the protective efficacy of the Moderna mRNA-1273 vaccine against BA.1 before or after boosting. Whereas two doses of mRNA-1273 vaccine induced high levels of neutralizing antibodies against historical WA1/2020 strains, lower levels against BA.1 were associated with breakthrough infection and inflammation in the lungs. A primary vaccination series with mRNA-1273.529, an Omicron-matched vaccine, potently neutralized BA.1 but inhibited historical or other SARS-CoV-2 variants less effectively. However, boosting with either mRNA-1273 or mRNA-1273.529 vaccines increased neutralizing titers and protection against BA.1 and BA.2 infection. Nonetheless, the neutralizing antibody titers were higher, and lung viral burden and cytokines were slightly lower in mice boosted with mRNA-1273.529 and challenged with BA.1. Thus, boosting with mRNA-1273 or mRNA-1273.529 enhances protection against Omicron infection with limited differences in efficacy measured.

Immune response to SARS-CoV-2 after a booster of mRNA-1273: an open-label phase 2 trial.

Rising breakthrough infections of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in previously immunized individuals have raised concerns for the need for a booster vaccine dose to combat waning antibody levels and new variants. Here we report the results of the open-label, non-randomized part B of a phase 2 trial in which we evaluated the safety and immunogenicity of a booster injection of 50 µg of the coronavirus disease 2019 (COVID-19) vaccine mRNA-1273 in 344 adult participants immunized 6-8 months earlier with a primary series of two doses of 50 µg or 100 µg of mRNA-1273 ( NCT04405076 ). Neutralizing antibody (nAb) titers against wild-type SARS-CoV-2 at 1 month after the booster were 1.7-fold (95% confidence interval (CI): 1.5, 1.9) higher than those at 28 days after the second injection of the primary series, which met the pre-specified non-inferiority criterion (primary immunogenicity objective) and might indicate a memory B cell response. The nAb titers against the Delta variant (B.1.617.2) (exploratory objective) at 1 month after the booster were 2.1-fold (95% CI: 1.8, 2.4) higher than those at 28 days after the second injection of the primary series. The seroresponse rate (95% CI (four-fold rise from baseline)) was 100% (98.7, 100.0) at 28 days after the booster compared to 98.3% (96.0, 99.4) after the primary series. The higher antibody titers at 28 days after the booster dose compared to 28 days after the second dose in the phase 3 COVE study were also observed in two assays for anti-spike IgG antibody measured by ELISA and by Meso Scale Discovery (MSD) Multiplex. The frequency of solicited local and systemic adverse reactions after the booster dose was similar to that after the second dose in the primary two-dose series of mRNA-1273 (50 µg or 100 µg); no new signals were observed in the unsolicited adverse events; and no serious adverse events were reported in the 1-month follow-up period. These results show that a booster injection of mRNA-1273 more than 6 months after completing the primary two-dose series is safe and elicited nAb titers that were statistically significantly higher than the peak titers detected after the primary vaccination series, suggesting that a booster dose of mRNA-1273 might result in increased vaccine effectiveness against infection and disease caused by SARS-CoV-2.

Protective activity of mRNA vaccines against ancestral and variant SARS-CoV-2 strains.

Although mRNA vaccines encoding the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prevent COVID-19, the emergence of new viral variants jeopardizes their efficacy. Here, we assessed the immunogenicity and protective activity of historical (mRNA-1273, designed for Wuhan-1 spike protein) or modified (mRNA-1273.351, designed for B.1.351 spike protein) Moderna mRNA vaccines in 129S2 and K18-hACE2 mice. Mice were immunized with either high-dose or low-dose formulations of the mRNA vaccines, where low-dose vaccination modeled suboptimal immune responses. Immunization with formulations at either dose induced neutralizing antibodies in serum against ancestral SARS-CoV-2 WA1/2020 and several virus variants, although serum titers were lower against the B.1.617.2 (Delta) virus. Protection against weight loss and lung pathology was observed with all high-dose vaccines against all viruses. However, low-dose formulations of the vaccines, which produced lower magnitude antibody and T cell responses, showed breakthrough lung infections with B.1.617.2 and development of pneumonia in K18-hACE2 mice. Thus, in individuals with reduced immunity after mRNA vaccination, breakthrough infection and disease may occur with some SARS-CoV-2 variants.

Variant SARS-CoV-2 mRNA vaccines confer broad neutralization as primary or booster series in mice.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of a global pandemic. Safe and effective COVID-19 vaccines are now available, including mRNA-1273, which has shown 94% efficacy in prevention of symptomatic COVID-19 disease. However, the emergence of SARS-CoV-2 variants has led to concerns of viral escape from vaccine-induced immunity. Several variants have shown decreased susceptibility to neutralization by vaccine-induced immunity, most notably B.1.351 (Beta), although the overall impact on vaccine efficacy remains to be determined. Here, we present the initial evaluation in mice of 2 updated mRNA vaccines designed to target SARS-CoV-2 variants: (1) monovalent mRNA-1273.351 encodes for the spike protein found in B.1.351 and (2) mRNA-1273.211 comprising a 1:1 mix of mRNA-1273 and mRNA-1273.351. Both vaccines were evaluated as a 2-dose primary series in mice; mRNA-1273.351 was also evaluated as a booster dose in animals previously vaccinated with mRNA-1273. The results demonstrated that a primary vaccination series of mRNA-1273.351 was effective at increasing neutralizing antibody titers against B.1.351, while mRNA-1273.211 was effective at providing broad cross-variant neutralization. A third (booster) dose of mRNA-1273.351 significantly increased both wild-type and B.1.351-specific neutralization titers. Both mRNA-1273.351 and mRNA-1273.211 are being evaluated in pre-clinical challenge and clinical studies.

Protection from SARS-CoV-2 Delta one year after mRNA-1273 vaccination in rhesus macaques coincides with anamnestic antibody response in the lung.

mRNA-1273 vaccine efficacy against SARS-CoV-2 Delta wanes over time; however, there are limited data on the impact of durability of immune responses on protection. Here, we immunized rhesus macaques and assessed immune responses over 1 year in blood and upper and lower airways. Serum neutralizing titers to Delta were 280 and 34 reciprocal ID50 at weeks 6 (peak) and 48 (challenge), respectively. Antibody-binding titers also decreased in bronchoalveolar lavage (BAL). Four days after Delta challenge, the virus was unculturable in BAL, and subgenomic RNA declined by ∼3-log10 compared with control animals. In nasal swabs, sgRNA was reduced by 1-log10, and the virus remained culturable. Anamnestic antibodies (590-fold increased titer) but not T cell responses were detected in BAL by day 4 post-challenge. mRNA-1273-mediated protection in the lungs is durable but delayed and potentially dependent on anamnestic antibody responses. Rapid and sustained protection in upper and lower airways may eventually require a boost.

Serum Neutralizing Activity of mRNA-1273 against SARS-CoV-2 Variants.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has led to growing concerns over increased transmissibility and the ability of some variants to partially escape immunity. Sera from participants immunized on a prime-boost schedule with the mRNA-1273 COVID-19 vaccine were tested for neutralizing activity against several SARS-CoV-2 variants, including variants of concern (VOCs) and variants of interest (VOIs), compared to neutralization of the wild-type SARS-CoV-2 virus (designated D614G). Results showed minimal, statistically nonsignificant effects on neutralization titers against the B.1.1.7 (Alpha) variant (1.2-fold reduction compared with D614G); other VOCs, such as B.1.351 (Beta, including B.1.351-v1, B.1.351-v2, and B.1.351-v3), P.1 (Gamma), and B.1.617.2 (Delta), showed significantly decreased neutralization titers ranging from 2.1-fold to 8.4-fold reductions compared with D614G, although all remained susceptible to mRNA-1273-elicited serum neutralization. IMPORTANCE In light of multiple variants of SARS-CoV-2 that have been documented globally during the COVID-19 pandemic, it remains important to continually assess the ability of currently available vaccines to confer protection against newly emerging variants. Data presented herein indicate that immunization with the mRNA-1273 COVID-19 vaccine produces neutralizing antibodies against key emerging variants tested, including variants of concern and variants of interest. While the serum neutralization elicited by mRNA-1273 against most variants tested was reduced compared with that against the wild-type virus, the level of neutralization is still expected to be protective. Such data are crucial to inform ongoing and future vaccination strategies to combat COVID-19.

Safety and immunogenicity of SARS-CoV-2 variant mRNA vaccine boosters in healthy adults: an interim analysis.

The emergence of SARS-CoV-2 variants of concern (VOCs) and variants of interest (VOIs) with decreased susceptibility to neutralization has generated interest in assessments of booster doses and variant-specific vaccines. Clinical trial participants who received a two-dose primary series of the COVID-19 vaccine mRNA-1273 approximately 6 months earlier entered an open-label phase 2a study ( NCT04405076 ) to evaluate the primary objectives of safety and immunogenicity of a single booster dose of mRNA-1273 or variant-modified mRNAs, including multivalent mRNA-1273.211. As the trial is currently ongoing, this exploratory interim analysis includes preliminary descriptive results only of four booster groups (n = 20 per group). Immediately before the booster dose, neutralizing antibodies against wild-type D614G virus had waned (P < 0.0001) relative to peak titers against wild-type D614G measured 1 month after the primary series, and neutralization titers against B.1.351 (Beta), P.1 (Gamma) and B.1.617.2 (Delta) VOCs were either low or undetectable. Both the mRNA-1273 booster and variant-modified boosters were safe and well-tolerated. All boosters, including mRNA-1273, numerically increased neutralization titers against the wild-type D614G virus compared to peak titers against wild-type D614G measured 1 month after the primary series; significant increases were observed for mRNA-1273 and mRNA-1273.211 (P < 0.0001). In addition, all boosters increased neutralization titers against key VOCs and VOIs, including B.1.351, P.1. and B.1.617.2, that were statistically equivalent to peak titers measured after the primary vaccine series against wild-type D614G virus, with superior titers against some VOIs. This trial is ongoing.

mRNA-1273 protects against SARS-CoV-2 beta infection in nonhuman primates.

B.1.351 is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant most resistant to antibody neutralization. We demonstrate how the dose and number of immunizations influence protection. Nonhuman primates received two doses of 30 or 100 µg of Moderna's mRNA-1273 vaccine, a single immunization of 30 µg, or no vaccine. Two doses of 100 µg of mRNA-1273 induced 50% inhibitory reciprocal serum dilution neutralizing antibody titers against live SARS-CoV-2 p.Asp614Gly and B.1.351 of 3,300 and 240, respectively. Higher neutralizing responses against B.1.617.2 were also observed after two doses compared to a single dose. After challenge with B.1.351, there was ~4- to 5-log10 reduction of viral subgenomic RNA and low to undetectable replication in bronchoalveolar lavages in the two-dose vaccine groups, with a 1-log10 reduction in nasal swabs in the 100-µg group. These data establish that a two-dose regimen of mRNA-1273 will be critical for providing upper and lower airway protection against major variants of concern.

Novel approaches for vaccine development.

Vaccines are critical tools for maintaining global health. Traditional vaccine technologies have been used across a wide range of bacterial and viral pathogens, yet there are a number of examples where they have not been successful, such as for persistent infections, rapidly evolving pathogens with high sequence variability, complex viral antigens, and emerging pathogens. Novel technologies such as nucleic acid and viral vector vaccines offer the potential to revolutionize vaccine development as they are well-suited to address existing technology limitations. In this review, we discuss the current state of RNA vaccines, recombinant adenovirus vector-based vaccines, and advances from biomaterials and engineering that address these important public health challenges.

COVID-19 vaccine mRNA-1273 elicits a protective immune profile in mice that is not associated with vaccine-enhanced disease upon SARS-CoV-2 challenge.

Vaccine-associated enhanced respiratory disease (VAERD) was previously observed in some preclinical models of severe acute respiratory syndrome (SARS) and MERS coronavirus vaccines. We used the SARS coronavirus 2 (SARS-CoV-2) mouse-adapted, passage 10, lethal challenge virus (MA10) mouse model of acute lung injury to evaluate the immune response and potential for immunopathology in animals vaccinated with research-grade mRNA-1273. Whole-inactivated virus or heat-denatured spike protein subunit vaccines with alum designed to elicit low-potency antibodies and Th2-skewed CD4+ T cells resulted in reduced viral titers and weight loss post challenge but more severe pathological changes in the lung compared to saline-immunized animals. In contrast, a protective dose of mRNA-1273 induced favorable humoral and cellular immune responses that protected from viral replication in the upper and lower respiratory tract upon challenge. A subprotective dose of mRNA-1273 reduced viral replication and limited histopathological manifestations compared to animals given saline. Overall, our findings demonstrate an immunological signature associated with antiviral protection without disease enhancement following vaccination with mRNA-1273.