Efficacy Study of COVID-19 mRNA Vaccine in Regions With SARS-CoV-2 Variants of Concern

Adverse events of special interest (AESI) were described in Appendix L of the protocol. AESI for this protocol include but are not limited to potential immune-mediated diseases.

Time frame: Up to Month 6

Population: FAS

The CDC-based COVID-19 endpoint is defined as the first occurrence of symptomatic NAAT-confirmed COVID-19 based on the following criteria: 1. At least ONE of the following systemic or respiratory symptoms: Fever (≥ 38C), chills, cough, shortness of breath and/or difficulty breathing, fatigue, muscle and/or body aches \[not related to exercise\], headache, new loss of taste/smell, sore throat, congestion, runny nose, nausea, vomiting, or diarrhea, AND 2. At least ONE (post-baseline) nasal swab (or respiratory sample, if hospitalized) positive for SARS-CoV-2 by NAAT. Because additional NAAT testing was performed at Month 1 for AG1 but not AG2-1, NAAT results at Month 1 were not considered. 3. The symptom date and NAAT positive date must be within 14 days of each other. The date of a COVID-19 endpoint according to the CDC-based definition is the earlier date of a symptom and the date of positive NAAT that satisfy the criteria stated above. The CDC criteria do not require adjudication.

Time frame: 1 day after Month 1 dose until Month 6 dose

Population: FAS

The COVE-based severe COVID-19 endpoint is defined as the first occurrence of a confirmed case of COVE-based COVID-19, plus any of the following: 1. Clinical signs indicative of severe systemic illness, Respiratory Rate ≥ 30 per minute, Heart Rate ≥ 125 beats per minute, SpO2 ≤ 93% on room air at sea level or PaO2/FIO2 less than 300 mm Hg, OR 2. Respiratory failure or Acute Respiratory Distress Syndrome (ARDS), (defined as needing high-flow oxygen, noninvasive or mechanical ventilation, or ECMO), evidence of shock (systolic blood pressure less than 90 mmHg, diastolic BP less than 60 mmHg or requiring vasopressors), OR 3. Significant acute renal, hepatic, or neurologic dysfunction, OR 4. Admission to an intensive care unit or death. The severe COVE criteria require adjudication.

Time frame: 1 day after Month 0 dose until Month 6 dose

Population: FAS

The COVE-based COVID-19 endpoint is defined as the first occurrence of adjudicated symptomatic NAAT-confirmed COVID-19 based on the following criteria (same as in the Moderna mRNA-1273 COVE trial): 1. At least TWO of the following systemic symptoms: Fever ≥ 38◦C), chills, myalgia, headache, sore throat, new loss of taste or smell, OR 2. At least ONE of the following respiratory signs/symptoms: cough, shortness of breath or difficulty breathing, OR clinical or radiographical evidence of pneumonia, AND 3. At least ONE (post-baseline) nasal swab (or respiratory sample, if hospitalized) positive for SARS-CoV-2 by NAAT. The date of a COVID-19 endpoint is the later date of a symptom and the date of positive NAAT. The COVE criteria require adjudication.

Time frame: 1 day after Month 0 dose until Month 6 dose

Population: FAS

An SAE is any AE that results in any of the following outcomes: death, a life-threatening adverse event, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, congenital anomaly/birth defect, or is medically important.

Time frame: Up to Month 6

Population: FAS

All solicited adverse events/reactogenicity symptoms are followed until resolution and graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, dated July 2017. Local reacto symptoms collected are: erythema/redness, induration/swelling, lymphadenopathy, and pain/tenderness. Systemic reacto symptoms collected are: arthralgia, chills, fever, headache, malaise/fatigue, myalgia, and nausea.

Time frame: Up to 7 days following Month 0 vaccination (all Study Groups) and up to 7 days following Month 1 vaccination (Study Groups 1 and 3)

Population: Safety subset.

All unsolicited AEs are graded according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017.

Time frame: Up to 28 days following Month 0 vaccination (all Study Groups) and up to 28 days following Month 1 vaccination (Study Groups 1 and 3)

Population: Safety subset.

Adverse events of special interest (AESI) were described in Appendix L of the protocol. AESI for this protocol include but are not limited to potential immune-mediated diseases.

Time frame: Day of Month 6 vaccination up to Month 18

Population: Participants who received a Month 6 vaccination, regardless of in or outside the randomization scheme, and with solicited and unsolicited AEs collected (FM6 cohort).

The CDC-based COVID-19 endpoint is defined as the first occurrence of symptomatic NAAT-confirmed COVID-19 based on the following criteria: 1. At least ONE of the following systemic or respiratory symptoms: Fever (≥ 38C), chills, cough, shortness of breath and/or difficulty breathing, fatigue, muscle and/or body aches \[not related to exercise\], headache, new loss of taste/smell, sore throat, congestion, runny nose, nausea, vomiting, or diarrhea, AND 2. At least ONE (post-baseline) nasal swab (or respiratory sample, if hospitalized) positive for SARS-CoV-2 by NAAT. 3. The symptom date and NAAT positive date must be within 14 days of each other. The date of a COVID-19 endpoint according to the CDC-based definition is the earlier date of a symptom and the date of positive NAAT that satisfy the criteria stated above. The CDC criteria do not require adjudication.

Time frame: 14 days after Month 6 dose until end of follow up (up to 18 months)

Population: Participants in FAS who received a Month 6 vaccination under the randomization scheme (RM6 cohort).

The COVE-based COVID-19 endpoint is defined as the first occurrence of adjudicated symptomatic NAAT-confirmed COVID-19 based on the following criteria (same as in the Moderna mRNA-1273 COVE trial): 1. At least TWO of the following systemic symptoms: Fever ≥ 38◦C), chills, myalgia, headache, sore throat, new loss of taste or smell, OR 2. At least ONE of the following respiratory signs/symptoms: cough, shortness of breath or difficulty breathing, OR clinical or radiographical evidence of pneumonia, AND 3. At least ONE (post-baseline) nasal swab (or respiratory sample, if hospitalized) positive for SARS-CoV-2 by NAAT. The date of a COVID-19 endpoint is the later date of a symptom and the date of positive NAAT. The COVE criteria require adjudication.

Time frame: 14 days after Month 6 dose until end of follow up (up to 18 months)

Population: Participants in FAS who received a Month 6 vaccination under the randomization scheme (RM6 cohort).

Statistical analyses were not performed because there are fewer than 7 severe COVE-based severe COVID-19 starting 14 days after Month 6 dose until end of follow up in RM6 cohort.

Time frame: 14 days after Month 6 dose until end of follow up (up to 18 months)

Population: Participants in FAS who received a Month 6 vaccination under the randomization scheme (RM6 cohort).

An SAE is any AE that results in any of the following outcomes: death, a life-threatening adverse event, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, congenital anomaly/birth defect, or is medically important.

Time frame: Day of Month 6 vaccination up to Month 18

Population: Participants who received a Month 6 vaccination, regardless of in or outside the randomization scheme, and with solicited and unsolicited AEs collected (FM6 cohort).

All solicited adverse events/reactogenicity symptoms are followed until resolution and graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, dated July 2017. Local reacto symptoms collected are: erythema/redness, induration/swelling, lymphadenopathy, and pain/tenderness. Systemic reacto symptoms collected are: arthralgia, chills, fever, headache, malaise/fatigue, myalgia, and nausea.

Time frame: Up to 7 days following Month 6 vaccination

Population: Participants in the safety subset who received a Month 6 vaccination, regardless of in or outside the randomization scheme, and with solicited and unsolicited AEs collected.

All unsolicited AEs are graded according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017.

Time frame: Up to 28 days following Month 6 vaccination

Population: Participants in the safety subset who received a Month 6 vaccination, regardless of in or outside the randomization scheme, and with solicited and unsolicited AEs collected.

Linear regression is used to provide covariate-adjusted point and 95% confidence interval estimation of geometric mean titers. Covariates adjusted are HIV status at baseline, age, sex at birth, and BMI.

Time frame: Month 0, 4 weeks post final pre-Month 6 vaccination (peak timepoint)

Population: Per-protocol serum immunogenicity set with antibody marker data available at Month 0 and peak timepoint. Hybrid immunity is defined by one pre-Month 6 immunization after natural infection. Vaccine-induced immunity is defined by two pre-Month 6 immunizations for baseline overall SARS-CoV-2 negative ppts. The purpose is to summarize NAb responses by vaccine regimen (hybrid vs vaccine), as well as within people living with HIV (PWH) and people living without HIV (PWoH) respectively.

Linear regression is used to provide covariate-adjusted point and 95% confidence interval estimation of geometric mean titers. Covariates adjusted are HIV status at baseline, age, sex at birth, and BMI.

Time frame: Month 0, 4 weeks post final pre-Month 6 vaccination (peak timepoint)

Population: Per-protocol serum immunogenicity set with antibody marker data available at Month 0 and peak timepoint. Hybrid immunity is defined by one pre-Month 6 immunization after natural infection. Vaccine-induced immunity is defined by two pre-Month 6 immunizations for baseline overall SARS-CoV-2 negative ppts. The purpose is to summarize NAb responses by vaccine regimen (hybrid vs vaccine), as well as within people living with HIV (PWH) and people living without HIV (PWoH) respectively.

Linear regression is used to provide covariate-adjusted point and 95% confidence interval estimation of geometric mean titers. Covariates adjusted are HIV status at baseline, age, sex at birth, and BMI.

Time frame: Month 0

Population: Per-protocol PBMC immunogenicity set with cellular marker data available at Month 0. Hybrid immunity is defined by one pre-Month 6 immunization after natural infection. Vaccine-induced immunity is defined by two pre-Month 6 immunizations for baseline overall SARS-CoV-2 negative ppts. The purpose is to summarize NAb responses by vaccine regimen (hybrid vs vaccine), as well as within people living with HIV (PWH) and people living without HIV (PWoH) respectively.

Linear regression is used to provide covariate-adjusted point and 95% confidence interval estimation of geometric mean titers. Covariates adjusted are HIV status at baseline, age, sex at birth, and BMI.

Time frame: 4 weeks post final pre-Month 6 vaccination (peak timepoint)

Population: Per-protocol PBMC immunogenicity set with cellular marker data available at Month 0. Hybrid immunity is defined by one pre-Month 6 immunization after natural infection. Vaccine-induced immunity is defined by two pre-Month 6 immunizations for baseline overall SARS-CoV-2 negative ppts. The purpose is to summarize NAb responses by vaccine regimen (hybrid vs vaccine), as well as within people living with HIV (PWH) and people living without HIV (PWoH) respectively.

The CDC-based COVID-19 endpoint is defined as the first occurrence of symptomatic NAAT-confirmed COVID-19 based on the following criteria: 1. At least ONE of the following systemic or respiratory symptoms: Fever (≥ 38C), chills, cough, shortness of breath and/or difficulty breathing, fatigue, muscle and/or body aches \[not related to exercise\], headache, new loss of taste/smell, sore throat, congestion, runny nose, nausea, vomiting, or diarrhea, AND 2. At least ONE (post-baseline) nasal swab (or respiratory sample, if hospitalized) positive for SARS-CoV-2 by NAAT. Because additional NAAT testing was performed at Month 1 for AG1 but not AG2-1, NAAT results at Month 1 were not considered. 3. The symptom date and NAAT positive date must be within 14 days of each other. The date of a COVID-19 endpoint according to the CDC-based definition is the earlier date of a symptom and the date of positive NAAT that satisfy the criteria stated above. The CDC criteria do not require adjudication.

Time frame: 1 day after Month 0 dose until Month 6 dose

Population: FAS. Participants who are baseline overall SARS-CoV-2 negative regardless of HIV status are comprised of Analysis Groups 1 and 3. Those who are baseline overall SARS-CoV-2 positive regardless of HIV status are comprised of Analysis Groups 2-1 and 4-1. Of note, overall SARS-CoV-2 status negative indicates all anti-Spike (anti-S), anti-Nucleocapsid (anti-N), and virus detection (NAAT) negative. Overall SARS-CoV-2 status positive indicates one of anti-S, anti-N, or NAAT positive.

The COVE-based COVID-19 endpoint is defined as the first occurrence of adjudicated symptomatic NAAT-confirmed COVID-19 based on the following criteria (same as in the Moderna mRNA-1273 COVE trial): 1. At least TWO of the following systemic symptoms: Fever ≥ 38◦C), chills, myalgia, headache, sore throat, new loss of taste or smell, OR 2. At least ONE of the following respiratory signs/symptoms: cough, shortness of breath or difficulty breathing, OR clinical or radiographical evidence of pneumonia, AND 3. At least ONE (post-baseline) nasal swab (or respiratory sample, if hospitalized) positive for SARS-CoV-2 by NAAT. The date of a COVID-19 endpoint is the later date of a symptom and the date of positive NAAT. The COVE criteria require adjudication.

Time frame: 1 day after Month 0 dose until Month 6 dose

Population: FAS. Participants who are baseline overall SARS-CoV-2 negative regardless of HIV status are comprised of Analysis Groups 1 and 3. Those who are baseline overall SARS-CoV-2 positive regardless of HIV status are comprised of Analysis Groups 2-1 and 4-1. Of note, overall SARS-CoV-2 status negative indicates all anti-Spike (anti-S), anti-Nucleocapsid (anti-N), and virus detection (NAAT) negative. Overall SARS-CoV-2 status positive indicates one of anti-S, anti-N, or NAAT positive.

The COVE-based severe COVID-19 endpoint is defined as the first occurrence of a confirmed case of COVE-based COVID-19, plus any of the following: 1. Clinical signs indicative of severe systemic illness, Respiratory Rate ≥ 30 per minute, Heart Rate ≥ 125 beats per minute, SpO2 ≤ 93% on room air at sea level or PaO2/FIO2 less than 300 mm Hg, OR 2. Respiratory failure or Acute Respiratory Distress Syndrome (ARDS), (defined as needing high-flow oxygen, noninvasive or mechanical ventilation, or ECMO), evidence of shock (systolic blood pressure less than 90 mmHg, diastolic BP less than 60 mmHg or requiring vasopressors), OR 3. Significant acute renal, hepatic, or neurologic dysfunction, OR 4. Admission to an intensive care unit or death. The severe COVE criteria require adjudication.

Time frame: 1 day after Month 0 dose until Month 6 dose

Population: FAS. Participants who are baseline overall SARS-CoV-2 negative regardless of HIV status are comprised of Analysis Groups 1 and 3. Those who are baseline overall SARS-CoV-2 positive regardless of HIV status are comprised of Analysis Groups 2-1 and 4-1. Of note, overall SARS-CoV-2 status negative indicates all anti-Spike (anti-S), anti-Nucleocapsid (anti-N), and virus detection (NAAT) negative. Overall SARS-CoV-2 status positive indicates one of anti-S, anti-N, or NAAT positive.

Time frame: Months 6 and 7

Population: Per-protocol serum immunogenicity set with antibody marker data available at Months 6 and 7. Hybrid immunity is defined by one pre-Month 6 immunization after natural infection. Vaccine-induced immunity is defined by two pre-Month 6 immunizations for baseline overall SARS-CoV-2 negative ppts.

The CDC-based COVID-19 endpoint is defined as the first occurrence of symptomatic NAAT-confirmed COVID-19 based on these criteria: 1. At least ONE of the following systemic or respiratory symptoms: Fever (≥ 38C), chills, cough, shortness of breath and/or difficulty breathing, fatigue, muscle and/or body aches \[not related to exercise\], headache, new loss of taste/smell, sore throat, congestion, runny nose, nausea, vomiting, or diarrhea, AND 2. At least ONE (post-baseline) nasal swab (or respiratory sample, if hospitalized) positive for SARS-CoV-2 by NAAT. 3. The symptom date and NAAT positive date must be within 14 days of each other. The date of a COVID-19 endpoint according to the CDC-based definition is the earlier date of a symptom and date of positive NAAT that satisfy the criteria stated above. The CDC criteria do not require adjudication.

Time frame: 14 days after Month 6 dose until end of follow up (up to 18 months)

Population: Participants in FAS who received a Month 6 vaccination under the randomization scheme (RM6 cohort) and have Month 6 hybrid immunity. Hybrid immunity is defined as any evidence of prior SARS-CoV-2 infection up to the Month 6 visit, defined by meeting any of the following criteria: 1) baseline overall SARS-CoV-2 status positive, 2) at least one NAAT result at or prior to Month 6 is positive, or 3) at least one anti-NP tests at or prior to Month 6 is positive.

The CDC-based COVID-19 endpoint is defined as the first occurrence of symptomatic NAAT-confirmed COVID-19 based on these criteria: 1. At least ONE of the following systemic or respiratory symptoms: Fever (≥ 38C), chills, cough, shortness of breath and/or difficulty breathing, fatigue, muscle and/or body aches \[not related to exercise\], headache, new loss of taste/smell, sore throat, congestion, runny nose, nausea, vomiting, or diarrhea, AND 2. At least ONE (post-baseline) nasal swab (or respiratory sample, if hospitalized) positive for SARS-CoV-2 by NAAT. 3. The symptom date and NAAT positive date must be within 14 days of each other. The date of a COVID-19 endpoint according to the CDC-based definition is the earlier date of a symptom and date of positive NAAT that satisfy the criteria stated above. The CDC criteria do not require adjudication.

Time frame: 14 days after Month 6 dose until end of follow up (up to 18 months)

Population: Participants in FAS who received a Month 6 vaccination under the randomization scheme (RM6 cohort) and have Month 6 vaccine immunity. Vaccine immunity is defined as absence of evidence of prior SARS-C

Participants were considered to have persistent SARS-CoV-2 NAAT positivity if they had positive swabs lasting \>= 50 days during a single infection. A single infection was assumed unless the participant had a positive NAAT following either a single negative NAAT by \>= 90 days or two consecutive negative NAATs over any time interval, in which case it was considered a reinfection. In Part A, the first NAAT+ on or before the Month 6 dose for each ppt was considered. In Part B, the first NAAT+ after the Month 6 dose for each ppt was considered. Analysis of viral evolution was not done due to termination of resources for evaluation.

Time frame: Participants testing positive for SARS-CoV-2 had additional nasab swabs taken fortnightly until testing negative, up to a maximum of 18 months

Population: Participants who are NAAT+ in the FAS cohort in part A. Participants who are NAAT+ in the RM6 cohort in part B.