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1.
Science ; 374(6573): 1343-1353, 2021 Dec 10.
Article in English | MEDLINE | ID: covidwho-1483979

ABSTRACT

Neutralizing antibody responses gradually wane against several variants of concern (VOCs) after vaccination with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine messenger RNA-1273 (mRNA-1273). We evaluated the immune responses in nonhuman primates that received a primary vaccination series of mRNA-1273 and were boosted about 6 months later with either homologous mRNA-1273 or heterologous mRNA-1273.ß, which encompasses the spike sequence of the B.1.351 Beta variant. After boost, animals had increased neutralizing antibody responses across all VOCs, which was sustained for at least 8 weeks after boost. Nine weeks after boost, animals were challenged with the SARS-CoV-2 Beta variant. Viral replication was low to undetectable in bronchoalveolar lavage and significantly reduced in nasal swabs in all boosted animals, suggesting that booster vaccinations may be required to sustain immunity and protection.


Subject(s)
/immunology , COVID-19 Vaccines/immunology , COVID-19/prevention & control , Immunogenicity, Vaccine , SARS-CoV-2/immunology , /administration & dosage , Animals , Antibodies, Neutralizing/blood , Antibodies, Viral/analysis , Antibodies, Viral/blood , Bronchoalveolar Lavage Fluid/immunology , Bronchoalveolar Lavage Fluid/virology , COVID-19/immunology , COVID-19/virology , COVID-19 Vaccines/administration & dosage , Immunity, Mucosal , Immunization, Secondary , Macaca mulatta , Nose/immunology , Nose/virology , RNA, Viral/analysis , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , T Follicular Helper Cells/immunology , Th1 Cells/immunology , Virus Replication
2.
Nat Immunol ; 22(10): 1306-1315, 2021 10.
Article in English | MEDLINE | ID: covidwho-1366822

ABSTRACT

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.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , Primates/immunology , SARS-CoV-2/immunology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/virology , Cell Line , Chlorocebus aethiops , Female , Humans , Macaca mulatta , Male , Mesocricetus , Primates/virology , RNA, Viral/immunology , Spike Glycoprotein, Coronavirus/immunology , Vaccination/methods , Vero Cells , Viral Load/methods
3.
Science ; 373(6561): eabj0299, 2021 Sep 17.
Article in English | MEDLINE | ID: covidwho-1334532

ABSTRACT

Immune correlates of protection can be used as surrogate endpoints for vaccine efficacy. Here, nonhuman primates (NHPs) received either no vaccine or doses ranging from 0.3 to 100 µg of the mRNA-1273 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. mRNA-1273 vaccination elicited circulating and mucosal antibody responses in a dose-dependent manner. Viral replication was significantly reduced in bronchoalveolar lavages and nasal swabs after SARS-CoV-2 challenge in vaccinated animals and most strongly correlated with levels of anti­S antibody and neutralizing activity. Lower antibody levels were needed for reduction of viral replication in the lower airway than in the upper airway. Passive transfer of mRNA-1273­induced immunoglobulin G to naïve hamsters was sufficient to mediate protection. Thus, mRNA-1273 vaccine­induced humoral immune responses are a mechanistic correlate of protection against SARS-CoV-2 in NHPs.


Subject(s)
Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/immunology , COVID-19/prevention & control , Immunogenicity, Vaccine , SARS-CoV-2/immunology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Antibody Affinity , Bronchoalveolar Lavage Fluid/immunology , Bronchoalveolar Lavage Fluid/virology , CD4-Positive T-Lymphocytes/immunology , COVID-19/immunology , COVID-19/virology , Female , Immunization Schedule , Immunization, Passive , Immunization, Secondary , Immunoglobulin G/immunology , Immunologic Memory , Lung/immunology , Lung/virology , Macaca mulatta , Male , Mesocricetus , Nasal Mucosa/immunology , Nasal Mucosa/virology , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/immunology , Vaccination , Vaccine Potency , Virus Replication
4.
Immunity ; 54(8): 1869-1882.e6, 2021 08 10.
Article in English | MEDLINE | ID: covidwho-1293864

ABSTRACT

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.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , COVID-19/prevention & control , Host-Pathogen Interactions/immunology , SARS-CoV-2/immunology , Vaccines, Synthetic/immunology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Biopsy , COVID-19 Vaccines/administration & dosage , Disease Models, Animal , Humans , Immunoglobulin G , Immunohistochemistry , Mice , Outcome Assessment, Health Care , RNA, Messenger , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Vaccines, Synthetic/administration & dosage
5.
N Engl J Med ; 383(16): 1544-1555, 2020 10 15.
Article in English | MEDLINE | ID: covidwho-680559

ABSTRACT

BACKGROUND: Vaccines to prevent coronavirus disease 2019 (Covid-19) are urgently needed. The effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines on viral replication in both upper and lower airways is important to evaluate in nonhuman primates. METHODS: Nonhuman primates received 10 or 100 µg of mRNA-1273, a vaccine encoding the prefusion-stabilized spike protein of SARS-CoV-2, or no vaccine. Antibody and T-cell responses were assessed before upper- and lower-airway challenge with SARS-CoV-2. Active viral replication and viral genomes in bronchoalveolar-lavage (BAL) fluid and nasal swab specimens were assessed by polymerase chain reaction, and histopathological analysis and viral quantification were performed on lung-tissue specimens. RESULTS: The mRNA-1273 vaccine candidate induced antibody levels exceeding those in human convalescent-phase serum, with live-virus reciprocal 50% inhibitory dilution (ID50) geometric mean titers of 501 in the 10-µg dose group and 3481 in the 100-µg dose group. Vaccination induced type 1 helper T-cell (Th1)-biased CD4 T-cell responses and low or undetectable Th2 or CD8 T-cell responses. Viral replication was not detectable in BAL fluid by day 2 after challenge in seven of eight animals in both vaccinated groups. No viral replication was detectable in the nose of any of the eight animals in the 100-µg dose group by day 2 after challenge, and limited inflammation or detectable viral genome or antigen was noted in lungs of animals in either vaccine group. CONCLUSIONS: Vaccination of nonhuman primates with mRNA-1273 induced robust SARS-CoV-2 neutralizing activity, rapid protection in the upper and lower airways, and no pathologic changes in the lung. (Funded by the National Institutes of Health and others.).


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/immunology , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/immunology , Pneumonia, Viral/prevention & control , Viral Vaccines/immunology , Animals , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Betacoronavirus/physiology , CD4 Antigens , COVID-19 , COVID-19 Vaccines , Coronavirus Infections/pathology , Coronavirus Infections/therapy , Disease Models, Animal , Dose-Response Relationship, Immunologic , Immunization, Passive , Lung/pathology , Lung/virology , Macaca mulatta , Pneumonia, Viral/pathology , Pneumonia, Viral/therapy , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , T-Lymphocytes/immunology , Viral Load , Viral Vaccines/administration & dosage , Virus Replication
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