These highlights do not include all the information needed to use

Administer a single dose (0.5 mL) of MRESVIA as an intramuscular injection.

MRESVIA is supplied as a pre-filled syringe that contains a frozen suspension that must be thawed prior to administration.

Thaw each syringe before use, either in the refrigerator or at room temperature, following the instructions in Table 1.

• After thawing, do not refreeze.
• Syringes should not be returned to the refrigerator after standing at room temperature.
• Pre-filled syringes may be stored at 8°C to 25°C (46°F to 77°F) for a total of 24 hours after removal from refrigerated conditions. Discard the thawed pre-filled syringe if not used within this time.
• Do not shake.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
• MRESVIA is a white to off-white suspension that may contain visible white or translucent product-related particulates. Do not administer if the vaccine is discolored or contains other particulate matter.

Administer MRESVIA intramuscularly.

Appropriate medical treatment must be immediately available to manage potential anaphylactic reactions following administration of MRESVIA.

Syncope (fainting) may occur in association with administration of injectable vaccines, including MRESVIA. Procedures should be in place to avoid injury from fainting.

Immunocompromised individuals, including those receiving immunosuppressive therapy, may have a diminished immune response to MRESVIA.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect the rates observed in practice.

Individuals 60 Years of Age and Older

The safety of MRESVIA was evaluated in Study 1 (NCT05127434), a placebo-controlled, observer blinded clinical study conducted in 22 countries that includes participants from North America/ Europe, Central/Latin America, Africa and Asian/Pacific regions. A total of 18,231 participants received MRESVIA and 18,181 received saline placebo (0.5 mL).

In Study 1, the median age of the participants was 67 years (range 60‑108 years). Overall, 51.0% of the participants were male, 49.0% were female, 33.6% were Hispanic or Latino, 61.8% were White, 12.0% were Black or African American, 11.0% were Asian, 4.9% were American Indian or Alaska Native, 0.1% were Native Hawaiian or Pacific Islander, 5.5% were other races, and 4.1% were Multiracial.

Demographic characteristics were comparable between participants who received MRESVIA and those who received placebo.

Solicited Adverse Reactions: Local and systemic adverse reactions (ARs) were solicited in an electronic diary (eDiary) for 7 days following injection (i.e., the day of injection and 6 subsequent days) among participants receiving MRESVIA (n=18,160) and participants receiving placebo (n=18,098). Events that persisted for more than 7 days were followed until resolution, but not to exceed 28 days after the study injection.

The percentage of participants who reported solicited local and systemic adverse reactions are presented in Table 2 and Table 3. Solicited local and systemic adverse reactions had a median duration of 1 to 2 days.

Unsolicited Adverse Events: Incidence of unsolicited adverse events, serious adverse events, and medically attended adverse events within 28 days of vaccination were similar in the groups that received MRESVIA or placebo. Unsolicited adverse events within 28 days considered related to the study vaccination were numerically higher in the recipients of MRESVIA (5.7%) than in the placebo recipients (4.4%), primarily attributed to events that were consistent with solicited adverse reactions.

There was a numerically higher incidence of urticaria in the MRESVIA group than the placebo group within 7 days post injection (8 and 2 participants, respectively) and within 28 days post injection (15 and 5 participants, respectively).

Serious Adverse Events: The median duration of safety follow-up was 311 days (range 1 to 585 days), and 96.6% of participants had at least a 6-month follow-up duration after vaccination. SAEs throughout the study were reported by 7.8% and 7.9% of participants in the MRESVIA group and the placebo group, respectively. One participant in the MRESVIA group had an SAE of facial paralysis with onset four days after vaccination assessed as related to MRESVIA. Within 28 days and 42 days post vaccination, there was no imbalance in reports of facial paralysis (including Bell’s palsy) between treatment groups. There were no other notable patterns or numerical imbalances between treatment groups for specific categories of serious adverse events that would suggest a causal relationship to MRESVIA.

Individuals 18 through 59 Years of Age at Increased Risk for LRTD Caused by RSV

The safety of MRESVIA was evaluated in Study 2 (NCT06067230) in which 502 participants aged 18 through 59 years at increased risk for LRTD caused by RSV received MRESVIA. Study 2 was conducted in the US, Canada and the United Kingdom.

From the day of vaccination (Day 1) through data cutoff for the safety analysis, the median duration of follow-up was 253 days (range: 8 to 349 days) in the MRESVIA group. As of the data cutoff date, 492/502 (98.0%) participants had completed at least 180 days of post-injection follow-up.

In Study 2, the median age of the participants in the MRESVIA group was 53.0 years (range 19‑59 years). Overall, 46.4% of the participants were male, 53.6% were female, 27.9% were Hispanic or Latino, 79.9% were White, 16.9% were Black or African American, 0.8% were Asian, 0.4% were American Indian or Alaska Native, 0.6% were Native Hawaiian or Pacific Islander, and 0.8% were Multiracial.

Conditions increasing the risk for RSV-LRTD were reported by the following percentages of participants in the MRESVIA group (individual participants may have reported more than 1 condition): diabetes mellitus (DM) in 59.6%, asthma in 38.8%, coronary artery disease (CAD) in 20.7%, chronic obstructive pulmonary disease (COPD) in 10.4%, congestive heart failure (CHF) in 9.0%, and chronic respiratory disease other than COPD or asthma in 2.4% of participants.

Solicited Adverse Reactions: Reactogenicity was assessed using a prespecified list of local and systemic adverse reaction terms that were actively solicited daily via eDiaries during the 7 days following vaccination (i.e., the day of vaccination and 6 subsequent days). The reported frequencies of specific solicited local and systemic adverse reactions among participants 18 through 59 years of age at increased risk for LRTD caused by RSV who received MRESVIA are presented in Table 4 and Table 5. Solicited local and systemic adverse reactions had a median onset of 2.0 days after vaccination and a median duration of 3 days.

Serious Adverse Events: Overall, by the data cutoff, serious adverse events were reported for 19 participants (3.8%) in Study 2. No SAEs were assessed as related to MRESVIA.

Risk Summary

All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

There are no human data to establish whether there is a vaccine associated risk with use of MRESVIA in pregnancy.

A developmental toxicity study was performed in female rats administered a vaccine formulation that included approximately twice the amount of nucleoside-modified messenger ribonucleic acid (mRNA), encoding the same RSV fusion (F) glycoprotein stabilized in the prefusion conformation, as in MRESVIA. The vaccine formulation was administered twice prior to mating and twice during gestation. The study revealed no evidence of harm to the fetus due to the vaccine (see Data).

Data

Animal Data

In a developmental toxicity study, 0.2 mL of a vaccine formulation containing 96 mcg of nucleoside‑modified mRNA per dose (a full human dose of MRESVIA contains 50 mcg of nucleoside‑modified mRNA) was administered to female rats by the intramuscular route on four occasions: 28 and 14 days prior to mating, and on gestation days 1 and 13. No vaccine‑related fetal malformations or variations and no adverse effects on postnatal development were observed in the study. The developmental toxicity study revealed no evidence of impaired female fertility.

Risk Summary

It is not known whether MRESVIA is excreted in human milk. No human or animal data are available to assess the effects of MRESVIA on the breastfed infant or on milk production/excretion.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for MRESVIA and any potential adverse effects on the breastfed child from MRESVIA or from the underlying maternal condition. For preventive vaccines, the underlying condition is susceptibility to disease prevented by the vaccine.

Safety and effectiveness of MRESVIA in individuals younger than 18 years of age have not been established.

In a dose-ranging study with ongoing follow-up, among infants vaccinated at 5 months through 7 months of age who received at least 1 dose of study vaccine (N=81), more cases of severe and/or hospitalized RSV lower respiratory tract disease (RSV-LRTD) were observed in those who received MRESVIA or an investigational vaccine containing MRESVIA components, compared with placebo recipients. All affected participants were RSV-seronegative at baseline. Based on analysis of data through two RSV seasons, the median duration of follow-up was 663 days (range 174 to 670 days). The time to onset between last study vaccination and occurrence of severe and/or hospitalized RSV-LRTD ranged from 3 to 466 days.

The observed imbalance in infants who were RSV-seronegative at baseline is considered consistent with an increased risk of severe LRTD due to natural RSV infection following receipt of MRESVIA or an investigational vaccine containing MRESVIA components as compared with placebo.

Of the total number of participants (N = 36,412) who received MRESVIA or placebo in Study 1 (NCT05127434), 22,554 (61.9%) were 60 to 69 years of age, 10,972 (30.1%) were 70 to 79 years of age, and 2,886 (7.9%) were 80 years of age and older [see Adverse Reactions (6.1) and Clinical Studies ( 14.1 )].

MRESVIA induces an immune response against RSV pre-F protein that protects against LRTD caused by RSV.

MRESVIA has not been evaluated for carcinogenic or mutagenic potential, or impairment of male fertility in animals.

Study 1 (NCT05127434) is a randomized, placebo‑controlled, observer‑blind, case‑driven clinical study to evaluate the safety and efficacy of MRESVIA to prevent RSV‑LRTD in individuals 60 years of age and older with or without underlying medical conditions after receipt of a single dose of MRESVIA. Study 1 is being conducted in 22 countries and includes participants from North America/ Europe, Central/Latin America, Africa, and Asian/Pacific regions and is designed to follow participants for up to 24 months after vaccination.

Participants were randomized to a single dose of MRESVIA or placebo (in a 1:1 ratio). Randomization was stratified by age (60 to 74 years; ≥75 years) and risk factors for LRTD, which were defined as congestive heart failure (CHF) and/or chronic obstructive pulmonary disease (COPD) at screening.

The primary efficacy analysis population [Per‑Protocol (PP) Efficacy Set] included 35,064 participants who received either MRESVIA (n=17,561) or placebo (n=17,503), with a data cutoff of 30 Nov 2022. This study population included 49.1% female, 50.9% male, 63.4% White, 12.2% Black or African American, 8.7% Asian, 5.1% American Indian or Alaska Native, and 10.6% other. Among participants, 34.7% identified as Hispanic or Latino. The median age of participants was 67 years (range 60‑96 years), with 30.9% of participants between 70 and 79 years and 5.6% of participants ≥80 years. There were no notable differences in demographics or pre‑existing medical conditions between participants who received MRESVIA and those who received placebo. A total of 7.0% had protocol-defined LRTD risk factors (CHF and/or COPD) and 29.5% had one or more comorbidity of interest (COPD, asthma, chronic respiratory disease, diabetes, CHF, advanced liver disease, or advanced renal disease).

Study exclusion criteria included history of myocarditis, pericarditis, or myopericarditis within 2 months prior to screening; autoimmune conditions requiring systemic immunosuppressants (stable HIV‑positive participants were permitted); history of serious reaction to any prior vaccination. Individuals were not eligible for inclusion in the Per-Protocol Efficacy Set if they received any other vaccine within 28 days before or after administration of the study injection.

The primary efficacy endpoints were the prevention of a first episode of RSV‑LRTD with either ≥2 signs/symptoms or ≥3 signs/symptoms starting 14 days after vaccination. RSV-LRTD was defined based on the following criteria: The participant must have had RT-PCR-confirmed RSV infection and experienced new or worsening of ≥2 (or ≥3) of the following signs/symptoms for at least 24 hours: shortness of breath, cough and/or fever (≥37.8°C [100.0°F]), wheezing and/or rales and/or rhonchi, sputum production, tachypnea (≥20 breaths per minute or increase of ≥2 breaths per minute from baseline measurement in those who have baseline tachypnea), hypoxemia (new oxygen saturation ≤93% or new or increasing use of supplemental oxygen), or pleuritic chest pain. If signs/symptoms could not be captured, radiologic evidence of pneumonia with RT-PCR-confirmed RSV infection was also counted as RSV-LRTD.

The primary efficacy analyses were performed when at least 50% of targeted RSV-LRTD cases had accrued [which occurred after a median of 3.7 months of follow-up (range 15 to 379 days) when 20.2% of participants had reached 6 months of follow-up]. Both primary efficacy analyses met the predefined success criterion (lower bound of the alpha-adjusted CI of the VE was >20%). Additional analyses of efficacy were performed after a median of 8.6 months of follow-up (range 15 to 530 days) when 94.2% of participants had reached 6 months of follow-up after vaccination and met the same success criterion (lower bound of the 95% CI of the VE was >20%). Analyses of efficacy for both timepoints are presented in Table 6.

Descriptive vaccine efficacy analyses by age subgroup and for participants with at least one comorbidity are presented in Table 7.

Study 2 evaluated the immunogenicity of MRESVIA in adults aged 18 through 59 years at increased risk for LRTD caused by RSV. Participants had documented confirmation of at least one of the following conditions: CAD and/or CHF, chronic lung disease (including but not limited to COPD or persistent asthma), and Type 1 or Type 2 DM. The demographic characteristics of participants in the Per-Protocol (PP) set in Study 2 were similar to those of the Safety Set. Effectiveness of MRESVIA in this population was assessed by comparison of neutralizing antibody (nAb) levels against the two major RSV subtypes, RSV-A and RSV-B, at Day 29 post-vaccination to those in a subset of Study 1 participants ≥60 years of age. The percentage of Study 1 subset participants who had at least one chronic medical condition (COPD, asthma, chronic respiratory disease, diabetes, CHF, advanced liver disease or advanced renal disease) was 57.2%.

In analyses of the primary endpoints, non-inferiority was demonstrated for the nAb Geometric Mean Titers (GMTs) for RSV-A and RSV-B [Study 2 PP/Study 1 Per-Protocol Immunogenicity (PPI) subset; lower bound of the 2‑sided 95% CIs of the Geometric Mean Ratio (GMR) > 0.667] (Table 8).

Seroresponse Rate Difference between Study 2 and Study 1 for Day 29 nAb (RSV-A and RSV-B)

Seroresponse for RSV-A and RSV-B nAb is defined as a post-primary dose titer ≥ 4 × LLOQ if baseline is < LLOQ or a ≥ 4-fold increase from baseline if baseline is ≥ LLOQ. The difference in seroresponse rate (SRR) for RSV‑A was 11.8% (95% CI: 7.8, 15.5) and for RSV-B was 10.8% (95% CI: 5.9, 15.6). These differences met prespecified non-inferiority criteria (lower bound of the 95% CI > -10%). Study 2 SRR (95% CI) at Day 29 for RSV-A was 85.8% (82.4, 88.7) and for RSV-B was 67.3% (62.9, 71.4). Study 1 SRR (95% CI) at Day 29 for RSV‑A was 74.0% (71.7, 76.2) and for RSV-B was 56.5% (53.9, 59.0).

MRESVIA is supplied as follows:

NDC 80777‑345‑62     Carton of 1 single‑dose pre-filled syringe in a paperboard tray. The syringe contains 1 dose of 0.5 mL (NDC 80777-345-01).

NDC 80777‑345‑90     Carton of 1 single‑dose pre-filled syringe in a blister pack. The syringe contains 1 dose of 0.5 mL (NDC 80777-345-01).

NDC 80777-345-63     Carton of 2 single-dose pre-filled syringes in a paperboard tray; each syringe contains 1 dose of 0.5 mL (NDC 80777-345-01).

NDC 80777-345-89     Carton of 2 single-dose pre-filled syringes in a blister pack; each syringe contains 1 dose of 0.5 mL (NDC 80777-345-01). Each carton contains 1 blister, and each blister contains two syringes. Use one syringe per dose.

NDC 80777‑345‑61     Carton of 10 single‑dose pre-filled syringes in a paperboard tray; each syringe contains 1 dose of 0.5 mL (NDC 80777-345-01).

NDC 80777‑345‑96     Carton of 10 single‑dose pre-filled syringes in a blister pack; each syringe contains 1 dose of 0.5 mL (NDC 80777-345-01). Each carton contains 5 blister packs, and each blister pack contains two syringes. Use one syringe per dose.

During storage, minimize exposure to room light, and avoid exposure to direct sunlight and ultraviolet light.

Frozen Storage

Store frozen between -40°C to ‑15°C (-40°F to 5°F).

Storage after Thawing

Storage at 2°C to 8°C (36°F to 46°F):

• Pre-filled syringes may be stored refrigerated between 2°C to 8°C (36°F to 46°F) for up to 90 days prior to use.

Storage at 8°C to 25°C (46°F to 77°F):

• Pre-filled syringes may be stored between 8°C to 25°C (46°F to 77°F) for a total of 24 hours after removal from refrigerated conditions. Discard the pre-filled syringe if not used within this time. Syringes should not be returned to the refrigerator after being thawed at room temperature.
• Total storage at 8°C to 25°C (46°F to 77°F) must not exceed 24 hours.
• Do not refreeze once thawed. Do not shake.

Transportation of Thawed Pre-filled Syringes

Thawed pre-filled syringes can be transported at 2°C to 8°C (36°F to 46°F) using shipping containers which have been qualified to maintain 2°C to 8°C (36°F to 46°F). Once thawed and transported at 2°C to 8°C (36°F to 46°F), pre-filled syringes should not be refrozen and should be stored at 2°C to 8°C (36°F to 46°F) until use.