August 29, 2025
6 min read
Every year, viral respiratory infections place a significant burden on the health care system.
The CDC predicts that influenza, respiratory syncytial virus and COVID-19 collectively will account for 27.3 million to 47.7 million outpatient visits, 1.1 million to 2.1 million hospitalizations and 73,000 to 207,000 deaths in the United States between October 2024 and September 2025, with direct and indirect costs in the billions of dollars.
Fortunately, multiple vaccines are available for these infections, as well as monoclonal antibody products (clesrovimab, nirsevimab) which provide infants with passive immunity against RSV. The CDC recommends annual influenza vaccination for all patients aged 6 months or older and a single dose of RSV vaccine for older adults and pregnant women at 32 to 36 weeks’ gestation.
Recommendations for COVID-19 vaccination continue to evolve, with some separation now between the CDC and other groups.
For instance, the American Academy of Pediatrics recommends routine COVID-19 vaccination for infants aged 6 to 23 months, children aged 2 to 18 years in certain risk groups, and pregnant adolescents. Both the AAP and CDC recommend COVID-19 vaccination for any child aged 6 months or older who is moderately or severely immunocompromised, but beyond that, the CDC’s recommendations call for shared clinical decision-making.
Additionally, the AAP and American College of Obstetricians and Gynecologists continue to recommend COVID-19 vaccination in pregnancy, breaking with federal recommendations announced earlier this year.
For influenza and RSV, ACIP recommendations suggest fall as the best time to administer vaccines. Understanding the interplay between virus seasonality and immune response can help clinicians further optimize the timing and administration of these vaccines to maximize their protective effects against respiratory illnesses.
A careful balance
Perhaps the single most important driver of vaccine timing for respiratory infections is the seasonality of respiratory viruses. In the continental U.S., the seasonal patterns of influenza and RSV are well-described, generally starting in October and lasting through April of the following year, with peaks from December to February. As SARS-CoV-2 transitions to an endemic virus, it is also expected to display seasonality. Current forecasts suggest either an annual peak in the winter or a large winter peak with smaller peaks in spring and summer are the most likely seasonal patterns of COVID-19 illness. With knowledge of these temporal trends in viral respiratory infections, clinicians can ensure patients are vaccinated prior to periods of greatest virus circulation and transmission.
Maximizing vaccine protection requires alignment of these viral seasonal patterns with the temporal course of vaccine immune response. Vaccines should be administered with sufficient time to allow effect before virus exposure occurs. Immune response to vaccination typically develops by 14 days; for influenza, RSV and COVID-19, vaccines have demonstrated antibody response within 2 to 4 weeks of administration.
However, not all vaccines exhibit durable responses. In recent years, numerous studies have demonstrated waning efficacy of influenza vaccines both between seasons and within a single season. In a meta-analysis of 14 studies of influenza vaccine effectiveness, Young and colleagues found that vaccine effectiveness decreased by 33% 3 to 6 months after vaccination. Currently available COVID-19 vaccines have also demonstrated waning effectiveness, with decreases of 21% to 38% by 6 months after vaccination, although waning immunity may have been exacerbated by mutations in circulating strains of SARS-CoV-2. Because they have only been on the market since 2023, less is known about the durability of RSV vaccines; however, currently available data indicate these vaccines maintain protection through at least two seasons.
Given the tension between time to vaccine response and durability, clinicians must carefully balance the need for early administration against providing sufficient duration of protection.
Unfortunately, there is little satisfactory evidence to guide a more precise timing of administration for these vaccines. Among influenza, RSV and COVID-19 vaccines, influenza vaccination is best studied.
In a health state transition model, Ferdinands and colleagues evaluated the tradeoffs of different influenza vaccine timing scenarios compared with actual immunization rates and timing observed in the U.S. in 2012-2013. In their model, delaying all vaccination until October increased influenza hospitalizations in most scenarios, as did significantly increasing the number of individuals vaccinated in August and September. However, the specific results for each scenario varied significantly based on assumptions regarding the timing of influenza season, vaccine effectiveness, and how quickly effectiveness waned. In contrast, a separate study by Newall and colleagues using alternative modeling approaches suggested that the optimal start time for influenza vaccine rollout was in September, with late September preferred for patients more likely so see rapid waning of effectiveness (for example, older adults and those with compromised immunity).
Similar modeling studies have not yet been conducted for RSV or COVID-19 vaccines. However, one recent paper on maternal RSV vaccination found that administration more than 5 weeks before delivery resulted in greater placental antibody transfer, and a separate study of maternal RSV vaccination found it had the greatest clinical utility at avoiding RSV-associated hospitalizations among infants when administered to pregnant women between September and December. Vaccination was most cost-effective when administered to pregnant women between September and November. These data, though limited, provide some hints for clinicians about ways to potentially optimize timing for influenza and maternal RSV vaccines.
Role of antigenic drift
A final consideration regarding immune response and the timing of respiratory virus vaccines is the role of antigenic drift. As mentioned above, mutations in COVID-19 likely amplified the waning of vaccine efficacy over time. Such mutations in circulating viruses, even in the absence of waning vaccine effectiveness, can necessitate repeat vaccination with reformulated products.
This antigenic drift is well-described with influenza and is another major reason why annual vaccination is necessary for this virus. A similar approach to COVID-19 vaccination may be beneficial. In a recent study of ensemble-based projections of COVID-19 illnesses, an annual COVID-19 vaccination program using formulations matched to circulating variants was projected to prevent 431,000 hospitalizations and 49,000 deaths in the U.S.
Conversely, RSV does not demonstrate significant antigenic drift, so the need for additional vaccinations will likely be driven by duration of immune response rather than viral mutations, and recommendations on repeat vaccination are likely to change as more is learned about the durability of RSV immunity.
Ideal timing?
Taken together, these data indicate that by promoting respiratory virus vaccines in the early fall, clinicians can leverage seasonality and immune dynamics to optimize vaccine timing to yield the greatest vaccine effectiveness.
As COVID-19 continues to transition to an endemic infection, a strategy of annual influenza and COVID-19 vaccination in September may maximize the benefits of vaccination for these infections. For older adults, it is unclear if RSV vaccination will eventually require more than one dose, but given the overlapping timing of RSV, influenza and potentially COVID-19 seasons, September administration of RSV vaccine to unvaccinated individuals is likely a reasonable approach.
These vaccines can be safely co-administered, so a single appointment in September for annual influenza, COVID-19, and possibly bi- or triennial RSV vaccines may be a convenient option for patients to receive these vaccines at the right time. For pregnant women, promoting RSV vaccination closer to 32 weeks’ gestation during RSV season may maximize vaccine effectiveness. However, in all scenarios, vaccination at any indicated time is preferred to no vaccination, so individual preferences and circumstances will also need to be considered.
In summary, through understanding the dynamics of seasonality and immunity, clinicians can develop a more nuanced plan for when to administer respiratory virus vaccinations. Influenza and RSV share overlapping seasons, and COVID-19 is expected to do the same. To maximize effectiveness during the respiratory virus season, fall administration of these vaccines is appropriate. Until additional evidence is available, co-administration of recommended respiratory virus vaccines in September may represent an ideal strategy for optimizing the timing of these vaccines.
References:
- Bonanni P, et al. Infect Dis Ther. 2025;doi:10.1007/s40121-025-01135-0.
- CDC. Immunization schedules. https://www.cdc.gov/vaccines/hcp/imz-schedules/index.html. Updated May 29, 2025. Accessed August 14, 2025.
- CDC. Preliminary estimated flu disease burden 2024-2025 flu season. https://www.cdc.gov/flu-burden/php/data-vis/2024-2025.html. Published May 9, 2025. Accessed Aug. 13, 2025.
- CDC. Preliminary estimates of COVID-19 burden for 2024-2025. https://www.cdc.gov/covid/php/surveillance/burden-estimates.html. Published Dec. 6, 2024. Accessed Aug. 13, 2025.
- CDC. Preliminary Estimates of RSV Burden for 2024-2025. https://www.cdc.gov/rsv/php/surveillance/burden-estimates.html. Published July 8, 2025. Accessed Aug. 13, 2025.
- Ferdinands JM, et al. Clin Infect Dis. 2020;doi:10.1093/cid/ciz452.
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- Menegale F, et al. JAMA Netw Open. 2023;doi:10.1001/jamanetworkopen.2023.10650.
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For more information:
Gregory B. Tallman, PharmD, MS, BCPS, BCIDP, is a clinical pharmacy specialist in infectious diseases and program director of the PGY2 infectious diseases pharmacy residency at Providence St. Joseph Health. He can be reached at gregory.tallman@providence.org.
