Phase III study sheds light on safety of RSV, flu, COVID-19 vax co-administration in adults

A two-part phase III study in adults aged ≥50 years supports the co-administration of the respiratory syncytial virus (RSV) vaccine, mRNA-1345, with the seasonal standard-dose quadrivalent inactivated influenza vaccine, SIIV4, or the bivalent COVID-19 vaccine, mRNA-1273.214.

“Co-administration of an RSV vaccine with influenza or SARS-CoV-2 vaccines could reduce healthcare visits and increase vaccination uptake in older adults who are at high risk for severe respiratory disease,” the investigators noted. However, co-administration could reduce the immunogenicity of the individual vaccines. [Hum Vaccin Immunother 2023;19:2195786]

“Overall, our results demonstrated that the co-administered vaccine regimens had acceptable safety profiles and elicited immune responses that were generally noninferior to those elicited by the individual vaccines,” they said.

RSV + flu vax

In part A of the study, 1,631 participants were randomized 7:10:10 to receive both mRNA-1345 50 µg (RSV vax) and SIIV4 60 µg (flu vax; co-admin arm), or either vaccine alone. The mean age across arms was 63.8 years and 54 percent were women. [Lancet Infect Dis 2024:S1473-3099(24)00589-9]

The rates of any solicited local adverse reactions reported within 7 days post-injection were similar between the co-admin and RSV vax alone arms (50 percent and 49 percent) and lower in the flu vax alone arm (29 percent). A similar pattern was observed for systemic adverse reactions (41, 40, and 32 percent, respectively).

The most common solicited grade 3 reaction was fatigue (2, 1, and 1 percent in the respective co-admin, RSV vax alone, and flu vax alone arms). In the RSV vax arm, one participant had grade 4 axillary swelling while another had fever.

The rates of unsolicited adverse events (AEs), irrespective of their association with vaccination, reported up to 28 days post-injection were similar across the co-admin, RSV vax alone, and flu vax alone arms (8, 8, and 7 percent, respectively), as were those of serious AEs (<1, 1, and 1 percent).

Of the six coprimary immunogenicity endpoints, five met the study’s prespecified noninferiority criterion: Geometric mean ratios (GMRs) of neutralizing antibodies (nAbs) against RSV-A in the co-admin vs RSV vax alone arm was 0.81, and the seroresponse rate difference in nAbs against RSV-A between groups was -11.2 percent. GMRs of anti-haemagglutination inhibition titres in the co-admin vs flu vax alone arm were 0.89, 0.97, 0.93, and 0.91 for the four influenza strains A/H1N1, A/H3N2, B/Victoria, and  B/Yamagata, respectively.

RSV + COVID vax

In part B, 1,691 participants were randomized 1:1:1 to receive the RSV vax and mRNA-1273.214 50 µg (COVID vax; co-admin arm), or either vax alone. The mean age was 62.5 years and 55 percent were women.

The rates of any solicited local adverse reactions were similar across arms (63, 57, and 57 percent for the respective co-admin, RSV vax alone, and COVID vax alone arms), and any systemic adverse reactions were numerically higher in the co-admin vs other arms (57 percent vs 46 percent and 48 percent).

According to the researchers, the slight difference in systemic adverse reactions was largely due to a slight increase in the rates of fatigue and myalgia in the co-admin vs the individual vax arms. In the COVID vax arm, one case of grade 4 fever was reported, but there were no grade 4 local adverse reactions.

All arms had few participants with AEs deemed vaccine-related by the investigator (<1, 1, and 1 percent in the respective co-admin, RSV vax alone, and COVID vax alone arms). According to the researchers, these were primarily reactogenicity and were nonserious.

The rates of unsolicited AEs, irrespective of their correlation to vaccination, reported within 28 days post-vaccination were numerically higher in the co-admin arm (10 percent) than in the COVID vax (8 percent) and RSV vax alone arms (7 percent). There were few participants reporting serious AEs in the co-admin (1 percent) and RSV vax alone arms (<1 percent), and none in the COVID vax alone arm. All serious AEs were deemed unrelated to the vaccination.

The GMR of nAbs against RSV-A in the co-admin vs RSV vax alone arms was 0.80, and the seroresponse rate difference was -4.4 percent. When comparing the co-admin arm with the COVID vax alone arm, the GMR of nAbs was 0.96 for the ancestral (D614G) virus and 1.00 for Omicron BA.1; seroresponse rate differences were 0.2 percent for D614G and -0.9 percent for Omicron BA.1.

“To our knowledge, this trial is the first to demonstrate the safety and immunogenicity of co-administered RSV and COVID-19 vaccines and that two different mRNA vaccines can be co-administered without a negative effect on the immune response to either vaccine,” the researchers noted.

Both parts

In both parts A and B, the co-administered vaccine regimens were well tolerated, with no serious AEs, AE of special interest, study discontinuations due to AEs, or fatal events deemed vaccine-related in any of the study arms during a median follow-up of about 6–7 months from receipt of injection at day 1.

There were also no cases of anaphylaxis, Guillan–Barre syndrome, acute disseminated encephalomyelitis, Bell’s palsy or facial paralysis, acute myocarditis, or pericarditis reported.

The most frequent local adverse reaction was injection site pain, and the most common systemic adverse reactions were fatigue, headache, and myalgia. Solicited adverse reactions were mostly grade 1–2 in severity, the researchers said.

Overlapping disease patterns

Older adults may be prone to RSV infections due to waning cellular immunity. [Clin Vaccine Immunol 2013;20:239–247] COVID-19 is a continuing issue, with epidemiological spikes in cases, hospital admissions, and mortality that generally overlaps with seasonal patterns reported for influenza and RSV in the northern hemisphere. [Sci Rep 2023;13:3886; MMWR Recomm Rep 2023; 72:1-25; https://www.who.int/teams/health-product-policy-and-standards/standards-and-specifications/norms-and-standards/vaccine-standardization, accessed 24 February 2025]

“Taken together, the results of this and other trials support co-administration vaccine approaches for these respiratory pathogens, which should improve vaccine uptake, reduce the burden of these respiratory diseases in older adults, [and encourage setting of relevant policies by regulatory agencies],” they concluded.

The investigators called for further studies to ascertain the longer-term safety and efficacy of co-administration of these vaccines across various populations, as well as evaluation of potential strategies for co-administration of all three vaccines together or given as a single, multicomponent vaccine. “[T]he mRNA platform has the flexibility to evaluate a multicomponent vaccine, if the need arises.”