Respiratory Virus Vaccines: Pathways to Recommendations and Enhanced Coverage for At-Risk Populations

Abstract

While marked differences exist between influenza virus, respiratory syncytial virus (RSV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there is substantial overlap in the vulnerability of populations most at risk for severe disease following infection, chief among them being advanced age, multiple comorbidities, and immunocompromise. Vaccination is an established and effective preventative strategy to protect against respiratory viral infections (RVIs), reducing morbidity and mortality, minimizing the potential for long-term complications, and mitigating exacerbation of existing health conditions. Despite the demonstrated benefits of immunization throughout the life course and recommendations by health authorities, coverage rates of at-risk populations against vaccine-preventable diseases remain suboptimal and vary considerably by country and demographic strata. The objective of this supplement’s concluding article is to discuss the current barriers to vaccination and strategies to enhance coverage against RVIs among adult at-risk populations. Identified barriers include low awareness of the risks of vaccine-preventable diseases, low perceived benefits of vaccination, and doubts regarding vaccine safety, which together contribute to vaccine hesitancy. Additionally, logistical issues related to vaccine supply, access, and costs present further challenges in achieving optimal coverage. Potential strategies to overcome these barriers and improve uptake include strengthening and harmonizing immunization guidelines and improving respiratory disease surveillance systems to appropriately identify needs and direct resources. Co-administration or use of combination vaccines against multiple viruses may be a viable strategy to enhance coverage by simplifying schedules and improving access, together with future utilization of enhanced vaccine platforms to develop novel vaccines. In addition, vaccination-focused healthcare provider training and consumer education are recommended to address vaccine hesitancy. Reaching vaccination targets and expanding coverage in adult at-risk populations are increasingly achievable with the availability of new and updated vaccination strategies for respiratory viruses, but will require collective efforts across providers, policymakers, scientists, health officials, and the general population.

Key Summary Points

Influenza virus, respiratory syncytial virus (RSV), and SARS-CoV-2 are respiratory viral infections that cause substantial morbidity and mortality, in particular among older adults, individuals with comorbidities, and individuals with immunocompromising conditions.

Vaccination is paramount to protect against severe illness caused by influenza virus, RSV, and SARS-CoV-2 infections to minimize long-term complications and mitigate exacerbation of existing health conditions; despite the demonstrated benefits, vaccination rates remain suboptimal in adult at-risk populations.

Challenges in achieving optimal vaccination coverage include low awareness of the disease risks, low perceived benefits of vaccination, doubts over vaccine safety, and logistical issues.

Potential strategies to overcome barriers and improve uptake include strengthening and harmonizing immunization guidelines, improving respiratory disease surveillance systems, and implementing vaccination-focused healthcare provider training and consumer education.

Co-administration of vaccines and administration of combination vaccines against multiple respiratory viruses are additional strategies to enhance coverage by simplifying immunization schedules and improving access.

Introduction

The projected global doubling of individuals aged ≥ 65 years over the next several decades [1] will result in an increase in the burden of vaccine-preventable diseases, especially respiratory viral infections (RVIs), in older adults [2]. RVIs from influenza virus, respiratory syncytial virus (RSV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), cause seasonal outbreaks and substantial morbidity and mortality [3]. While marked differences exist between these three viruses, there is significant overlap in the populations most at risk from infection-related severe illness and long-term complications, including those of advanced age, with multiple comorbidities or immunocompromise, and specific racial and socioeconomic disparities [4–7].

Implementing effective vaccination strategies is paramount to directly protect against severe illness caused by influenza virus, RSV, and SARS-CoV-2 infections, toward minimizing the potential for long-term complications and mitigating exacerbation of existing health conditions [8]. Although herd immunity may reduce the risk of infection, it is insufficient to prevent severe outcomes following infection; therefore, vaccines are especially critical for at-risk populations to reduce the risk of severe illness [9]. The direct and indirect benefits of vaccines resulting from large-scale immunization programs can be observed throughout the life course [10]. However, vaccination coverage rates of older adults against vaccine-preventable diseases are well below targets recommended by the World Health Organization (WHO) [11]. Concerted efforts are therefore needed to improve coverage by targeting the multiple components that underpin suboptimal vaccination rates in adult at-risk populations.

In this concluding article of the supplement, we summarize the key messages of the previous articles that describe the burden, risk factors, and impact of vaccination for influenza, RSV, and SARS-CoV-2 infection in at-risk populations. We discuss the current barriers to optimal vaccination coverage and propose strategies to enhance this coverage against RVIs in at-risk populations. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Vaccine-Preventable RVIs: Burden, Risk Factors, and Vaccination in At-Risk Populations

The previous articles in this supplement review the burden of the vaccine-preventable RVIs influenza, RSV, and SARS-CoV-2 in at-risk populations. Risk factors for severe illness following infection and the impact of vaccination on RVI-related outcomes are also discussed, highlighting older adults and individuals with chronic and immunocompromising conditions. Development of vaccines against respiratory viruses in these vulnerable populations is explored, including implementation of co-administration and combination vaccine strategies for simultaneous protection.

Influenza, RSV, and SARS-CoV-2 infection and disease in older adults are associated with a considerable burden, including long-lasting consequences such as functional decline, disability, and mortality. In addition to the clinical burden, RVIs also place a substantial financial strain on individuals, society, and healthcare systems. Those with chronic and immunocompromising conditions are recognized as being at-risk for severe disease following RVIs, independent of their age. Establishing a thorough understanding of the risk factors for severe illness could facilitate the development of effective mitigation strategies, such as vaccination for high-risk populations, and help to inform decision-making among healthcare providers (HCPs) and public health officials. The overall beneficial impact of vaccination against these RVIs extends beyond direct prevention of disease, to providing protection against long-term progression toward downstream comorbidities or exacerbation of existing conditions. The far-reaching positive societal outcomes, which are not always quantifiable or recognized, support the development of new vaccine platforms and address challenges with vaccine uptake.

Barriers to Optimal Vaccination Coverage

Vaccine Recommendations and Uptake

Current WHO, European Centre for Disease Prevention and Control (ECDC), and US Centers for Disease Control and Prevention (CDC) vaccine recommendations for at-risk populations are outlined in Table 1 [12–16]. The specific rationale underlying each vaccine recommendation varies by respiratory virus, at-risk population, and health authority; in general, such recommendations are based on clinical trial and observational real-world data that support enhanced protection and reduction in severe illness, hospitalization, and death. For example, the rationale for an RSV vaccine in adults aged ≥ 60 years is based on evidence from clinical trials demonstrating moderate to high efficacy in preventing symptomatic RSV-associated lower respiratory tract disease over two RSV seasons, with data to suggest a potential reduction in RSV-associated morbidity [17]. In immunocompromised populations, COVID-19 vaccination recommendations are considered the most effective strategy to prevent serious outcomes and death following SARS-CoV-2 infection, even in the context of a blunted immune response [18]. Administration of additional doses of a COVID-19 vaccine in at-risk populations is recommended to enhance protective immunity, with evidence demonstrating increased cell-mediated responses in immuno-compromised and elderly individuals, including in those who were poor responders to the primary vaccination series [19].

Table 1.

2023–2024 Vaccine recommendations in at-risk populations by select recommending bodies

Recommending body	Older adults	Considerations for other at-risk populations
Influenza virus vaccine
CDC [12]	HD-IIV4, RIV4, or aIIV4 in adults aged ≥ 65 years	LAIV4 not recommended for persons with chronic medical conditions, including underlying medical conditions that might predispose to complications from influenza (e.g., chronic pulmonary, cardiovascular, renal, hepatic, neurologic, hematologic, and metabolic disorders, and immunocompromised individuals)
ECDC [13]a	IIV, IIV3, or IIV4 in adults aged ≥ 65 years depending on country	IIV, IIV3, or IIV4 depending on at-risk population and country
WHO [14]	IIV3 or IIV4 in adults LAIV not recommended for older adults	LAIV not recommended for those with comorbidities
RSV vaccine
CDC [12]	RSV vaccine recommended for adults 60–74 years of age who are at risk of severe RSV disease as a single lifetime dose RSV vaccine recommended in adults ≥ 75 years of age as a single lifetime dose	Individuals at increased risk for severe RSV disease include those with chronic medical conditions, including cardiovascular disease, lung disease, neurologic or neuromuscular conditions, kidney disorders, liver disorders, hematologic disorders, diabetes mellitus, and moderate or severe immune compromise; those who are frail or residents of nursing homes or other long-term care facilities; and those with other underlying medical conditions or factors that may increase the risk of severe respiratory disease
ECDC [13]a	RSV vaccine in adults aged > 60 years in Austria and adults aged ≥ 75 years in Sweden	RSV vaccine in adults with comorbidities plus aged > 60 years in Belgium and Sweden
WHO [14]	Not specified	Not specified
COVID-19 vaccine
CDC [12, 15]	COVID-19 vaccine (2023/2024 formulation) in adults, with varied recommendations based on prior vaccination status and vaccine type Additional dose of COVID-19 vaccine (2023/2024 formulation) in adults aged ≥ 65 years	COVID-19 vaccine (2023–2024 formulation), with varied schedule based on prior vaccination status and vaccine type in those with moderate or severe immunocompromising conditions Option for an additional dose of COVID-19 vaccine (2023–2024 formulation) ≥ 2 months following the last recommended COVID-19 vaccine (2023–2024 formulation) in those with moderate or severe immunocompromise
ECDC [13]a	COVID-19 vaccine in adults aged ≥ 65 years in all countries except Cyprus	Not specified
WHO [16]	COVID-19 vaccine in previously unvaccinated adults COVID-19 revaccination in previously vaccinated adults aged ≥ 75 years and in adults aged ≥ 50 years, with varied vaccine schedule depending on population COVID-19 revaccination not recommended for previously vaccinated healthy adults	COVID-19 vaccine in previously unvaccinated immunocompromised individuals COVID-19 revaccination in previously vaccinated adults with comorbidities plus aged ≥ 50 years, immunocompromised individuals, and adults with comorbidities regardless of age, with varied vaccine schedule depending on population

a adjuvanted, CDC Centers for Disease Control and Prevention, COVID-19 coronavirus disease 2019, ECDC European Centre for Disease Prevention and Control, HD high dose, IIV inactivated influenza vaccine, LAIV live attenuated influenza vaccine, RIV recombinant influenza vaccine, RSV respiratory syncytial virus, WHO World Health Organization, 3 trivalent vaccine, 4 quadrivalent vaccine

^aEuropean countries include Austria, Belgium, Bulgaria, Croatia, Cyprus, Czechia, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Liechtenstein, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, and Sweden

Despite global health authorities’ recommendations, there is considerable variation in vaccination rates of respiratory vaccine uptake by country. Before the COVID-19 pandemic, median seasonal influenza vaccination coverage in Europe in 2016–2017 was 47.1% (range 2.0–72.8%) for older adults across 19 countries, and 44.9% (range 15.7–57.1%) for individuals with chronic medical conditions across 7 countries [20]. These median coverage rates increased in 2020–2021 to 59.0% (range 4.5–75.0%) for older adults across 19 countries and 55% (range 25.8–77.0%) for individuals with chronic medical conditions across 4 countries [21]. By comparison, among older adults in the United States, influenza vaccine coverage was 69.3% (95% CI 66.4–72.2%) in fall 2023 [22], increasing marginally to 74.4% (95% CI 72.8–76.0) by March 2024 [23]. For the majority of countries, influenza vaccine uptake rates remain below the historical goals set forth by the 2003 World Health Assembly Resolution, which aimed to attain influenza vaccination coverage of 75% among the elderly by 2010 and to increase influenza vaccination coverage of individuals at elevated risk [24]. Data collection on uptake of recently approved RSV vaccines is ongoing; therefore, comparison of country-specific trends is limited. Available data in the United States demonstrate that self-reported RSV vaccine coverage among older adults aged ≥ 60 years was 17.0% (95% CI 15.7–18.3%) in 2023 [22] and 23.8% (95% CI 22.8–24.8%) in 2024 [23].

Regarding uptake of the Omicron XBB.1.5-containing COVID-19 updated vaccine, median coverage in Europe from September 2023–January 2024 was 11.1% among adults aged ≥ 60 years (range 0.01–65.8%) and 16.3% (0.01–88.2%) among adults aged ≥ 80 years, with high variation across countries; only 3 of 24 reporting countries attained coverage of ≥ 50% for older adults [25]. In that same report, coverage among individuals with chronic conditions was low and reported by 2 countries (Czechia 1.9% and Spain 5.4%) [25]. In the United States, self-reported COVID-19 vaccine coverage among adults aged ≥ 65 years during fall 2023 was 37.4% (95% CI 35.1–39.6%) [22] and increased in 2024 to 42.1% (95% CI 40.8–43.5) [23]. Similarly, in Canada as of February 2024, 38% of adults aged 60–69 years were vaccinated per recommendations, with higher coverage in older age groups (aged 70–79 years, 54.6%; aged ≥ 80 years, 60.9%) [26].

In addition to the variation in RVI vaccination rates by country, there is also substantial variation in coverage across demographic strata, with disparities by race and ethnicity, highlighting the need to consider vulnerable populations when planning and rolling out RVI vaccination programs. A systematic review of European and American studies published in 2020–2021 found significant associations between COVID-19 vaccine uptake during the early stage of vaccine availability and multiple social determinants of health, with increased coverage in Asian and white populations and lower coverage in the Black population [27]. Lower uptake rates among native racial or ethnic populations have also been observed despite high vaccination rates in the general and non-Indigenous populations in their respective countries, including the Indigenous Peoples of Canada [28–30] and Aboriginal and Torres Strait Islander Communities in Australia [31, 32].

Racial or ethnic uptake trends are also evident for other RVIs. For instance, in the United States in 2023, influenza vaccine coverage was higher among non-Hispanic white and non-Hispanic Asian adults, and updated COVID-19 and RSV vaccination coverage rates were higher among white adults compared with most other racial and ethnic groups [22].

Underestimation of True Disease Burden and Impact of Vaccination

Surveillance of RVIs is crucial for managing and preventing associated respiratory disease [33–35]. While the COVID-19 pandemic saw the rapid scale up of existing respiratory surveillance measures and implementation of novel activities such as COVID-19 prevalence surveys, these measures are unlikely to be feasible for nonemergency surveillance, as evidenced by the scaling back of COVID-19 monitoring in many countries as they transition out of the pandemic [33]. In addition, as social disruption from COVID-19 has decreased globally, influenza and RSV are resuming seasonal circulation patterns [33, 36, 37].

The cocirculation of SARS-CoV-2, influenza, and RSV is expected to place substantial pressure on healthcare systems; therefore, effective integrated surveillance systems for all three viruses are crucial for monitoring their spread and guiding control measures to mitigate their impact [33, 34]. Many countries have already implemented or are planning to implement integrated sentinel surveillance for SARS-CoV-2, influenza, and RSV [33, 38]; however, in a survey of 29 European countries by the ECDC, less than half responded that they have implemented or plan to implement surveillance of vaccine effectiveness [38]. More than half of surveyed countries anticipate barriers to implementing integrated sentinel surveillance of RVIs in primary care, while most (72.4%) anticipate barriers in secondary care [38]. Identified barriers included a lack of infrastructure and resources, as well as legislative issues and potential issues with data quality from new systems [38].

In the absence of accurate surveillance systems to collect epidemiologic data on RVIs and assess vaccine effectiveness in at-risk populations, the true burden of RVI disease and the impact of vaccination may be underestimated. Inaccurate burden estimates may also prevent local health authorities from directing resources to where they are most needed. Greater investment in surveillance of RVI disease burden and assessment of vaccine effectiveness are therefore required to adequately evaluate the impact of RVI vaccination in at risk-groups.

General Lack of Awareness on the Continued Benefits of Adult Vaccination Programs

Lack of awareness of the risks of vaccine-preventable diseases and the benefits of vaccination, as well as doubts surrounding vaccine safety, are among the key determinants of vaccine hesitancy [39] and have been identified as barriers of routine vaccination in older adults [40]. In a systematic literature review of drivers and barriers of routine vaccination uptake globally in adults aged ≥ 50 years, awareness or knowledge of vaccine-preventable diseases and vaccine availability was positively associated with vaccination [40]. In one cross-sectional survey of 1223 older German adults (aged 60–85 years), participants who had a high knowledge score for seasonal influenza vaccination were 30% more likely to be vaccinated than those with a lower knowledge score [odds ratio (OR) 1.3, 95% CI 1.0–1.6; p = 0.02] [41]. In addition, results from a cross-sectional study of 230 older adults (aged ≥ 65 years) admitted to hospital in Poland indicated that patients who were informed about influenza vaccination were five times more likely to be vaccinated than those who were uninformed about vaccination (OR 5.00, 95% CI 1.23–33.89) [42]. The primary reasons cited for not being vaccinated in this study were a lack of belief in vaccine efficacy (67.8%), followed by a poorly tolerated previous vaccination (38.4%), and lack of information on vaccination (23.0%) [42].

Perceptions of personal risk and disease severity have both been shown to be predictors of routine vaccination uptake in older adults, with perceived low risk of disease susceptibility associated with non-vaccination [40]. In a qualitative study of the attitudes and perceptions of 15 older adults (aged ≥ 66 years) in Singapore toward influenza vaccination, reasons for not accepting influenza vaccination included a perceived lack of susceptibility to influenza infection and a perceived inevitability of illness in older age [43].

Similar findings have been reported for additional doses of COVID-19 vaccines, with a cross-sectional survey of 2004 adults aged ≥ 50 years in England identifying knowledge and perceived susceptibility to COVID-19 as key determinants of decision-making [44]. In that study, multivariate logistic regression modeling showed that compared with individuals who accepted an additional COVID-19 dose, vaccine knowledge was negatively associated with not having thought about additional doses [unengaged; adjusted relative risk (RR) 0.384, 95% CI 0.275–0.537; p < 0.001] and being undecided (RR 0.510, 95% CI 0.391–0.665; p < 0.001), while perceived lack of susceptibility to COVID-19 was positively associated with not having thought about additional doses (RR 1.927, 95% CI 1.472–2.522; p < 0.001) and being undecided (RR 1.383, 95% CI 1.142–1.676; p < 0.001) [44].

While most adults are aware of COVID-19 and influenza, a cross-sectional survey of 827 US adults at increased risk of RSV (aged ≥ 60 years and aged 18–59 years with comorbidities) revealed that less than half (43.3%) had heard of RSV, while only 34.6% of those who had heard of RSV reported being knowledgeable about the virus [45]. Questionnaire responses revealed that there were substantial RSV knowledge gaps, including its viral nature, seasonality, symptoms, and diagnosis in clinical practice [45]. Similarly, cross-sectional surveys of HCPs have revealed a low awareness of the burden of RSV-associated disease among adults and of the recent availability of vaccines against RSV lower respiratory tract infection [46, 47]. In a survey of 317 US primary care physicians with experience in caring for adults with RSV, 57% responded that they rarely consider RSV as a potential pathogen in patients aged ≥ 50 years with a respiratory disease, while 86% responded that they needed more information on the burden of RSV disease [46]. A recent survey of 154 cardiology HCPs in Italy, following availability of the adjuvanted recombinant RSVPreF3 and bivalent recombinant subunit RSV vaccines, highlighted low awareness of the consequences and complications of RSV infections, and of the availability of RSV vaccines, with < 50% of HCPs being knowledgeable about newly available RSV vaccines [47]. Significantly, multivariate regression modeling demonstrated that willingness to recommend RSV vaccination to patients was associated with knowledge about new RSV vaccines (OR 3.82, 95% CI 1.18–12.36; p = 0.03) [47]. In addition, the majority of HCPs responded that they need more information on RSV vaccines and vaccination in older adults and patients with comorbidities [47]. Information and education for HCPs on the benefits of routine vaccination in older adults and at-risk populations, and on the availability of vaccines are vital, given that HCP recommendation for vaccination is a strong predictor of vaccine uptake among vulnerable populations [40, 42].

Collectively, findings from studies on barriers and drivers of routine vaccination uptake in older adults highlight the importance of providing those individuals and other at-risk populations with detailed information on the benefits of vaccination against RVIs [42, 44], as well as continuing education on both the burden of RVI disease and availability of vaccines among HCPs [46, 47].

Vaccine Hesitancy and Literacy

An additional barrier to optimal RVI vaccine coverage is vaccine hesitancy, defined as a delay in acceptance of vaccination or altogether refusal despite vaccine availability, which is complex and driven by numerous factors that influence behavior [48]. In the three Cs model of vaccine hesitancy, the decision to be vaccinated is affected by confidence (i.e., trust in vaccine safety/effectiveness, healthcare systems, and health policymakers), complacency (i.e., perceived risk of vaccine-preventable diseases), and convenience (e.g., vaccine availability, affordability, accessibility, quality of service) [48]. Vaccine hesitancy determinants can be contextual, arising from historical, cultural, environmental, health, economic, or political influences; individual and group, arising from personal perception or the social environment; and vaccine-/vaccination-specific, arising from concerns directly related to the vaccine itself or vaccination in general [48].

In the older adult population, vaccine hesitancy is associated with various sociodemographic, health-related, and attitudinal factors, as well as previous vaccine experiences [40, 44]. In a systematic literature review on general vaccination in individuals aged ≥ 50 years, a bachelor’s degree (but not a high school education or master’s or higher degree) and poor perceived health levels were associated with increased vaccine hesitancy; being vaccine hesitant was negatively associated with influenza vaccine uptake [40]. In that same review, experience or expectation of vaccine-related adverse side effects was a perceived barrier to vaccination across several studies [40]. Similarly, results from a cross-sectional study in adults aged > 50 years in England suggested that negative past experiences with the COVID-19 primary vaccine series may lead to additional dose hesitancy [44].

Health literacy comprises an individual’s knowledge, motivation, and competence to identify, comprehend, and utilize information regarding healthcare, disease prevention, and health promotion for appropriate decision-making [49]. Similarly, vaccine awareness is defined as having relevant and sufficient immunization information [50]. Together, health literacy and vaccine awareness have been identified as factors that influence consideration of vaccination in disadvantaged, isolated, and difficult-to-reach communities in the WHO European region countries [51]. Findings from a systematic literature review indicated that individuals were unable to locate, understand, or use reliable information and services for vaccines, with language barriers playing a role [51].

Improvements in vaccine literacy, a concept similar to health literacy but specific to immunization, have been proposed to address vaccine hesitancy [49]. A review of 39 global articles evaluating vaccine literacy and COVID-19 found that the primary contributors were age, gender, education level, marital status, and socioeconomic status; aging in particular was associated with higher vaccine literacy [49].

Logistical Issues Related to Vaccine Delivery to Target At-Risk Populations

Insufficient supplies of age-specific vaccines have occurred on several occasions due to companies exiting the infectious disease/vaccine space, problems with vaccine manufacturing or production, limited vaccine stockpiles, and other reasons, necessitating temporary changes in immunization schedule recommendations [52]. Historically, in the United States in the 2003–2004 influenza season, a sudden shortage in the national influenza vaccine supply resulted in a shift in the CDC’s vaccination recommendations; healthy individuals aged 2– 64 years were requested to forego immunization to reserve vaccine doses for the highest at-risk populations, including older adults aged ≥ 65 years and individuals with chronic medical conditions or immunosuppression [53]. In a related example, in the United States in the 2023–2024 RSV season, a shortage of a monoclonal antibody that provides passive immunization to prevent RSV disease in infants resulted in a CDC health advisory regarding interim recommendations to reserve supplies for the highest at-risk infant population [54].

In addition to logistical issues related to vaccine supply, cost-related barriers to vaccine access present a challenge. A systematic literature review of factors influencing routine vaccination in older adults found that vaccine affordability and health insurance coverage had a positive impact on vaccination in various countries [40]. Ensuring affordability through insurance coverage or public funding can lessen financial constraints [40]. During the COVID-19 pandemic, governments made substantial investments to support availability of COVID-19 vaccines at zero cost to the patient to support access; however, concerns have mounted over anticipated cost-sharing for vaccines as we transition to a post-pandemic state, with vaccine pricing through the private sector and shifts in insurance coverage [55]. Recent 2023 data of RVI vaccination coverage in the United States revealed significantly lower uptake among uninsured compared with insured adults [5 (95% CI) uninsured vs. insured: 17.8% (15.6–19.9%) vs. 45.4% (44.2–46.6%) for influenza; 4.3% (3.3–5.4%) vs. 20.0% (19.1–20.9%) for COVID-19; 3.3% (1.1–5.5%) vs. 17.6% (16.2–18.9%) for RSV] [22].

Strategies to Enhance COVID-19, Influenza, and RSV Vaccine Coverage in At-Risk Populations

Strengthening and Harmonization of Vaccination Guidelines for RVIs

Strengthening and harmonizing vaccination guidelines for RVIs in at-risk populations will be vital to realize the WHO vision of a world where individuals of every age benefit from recommended vaccines [56]. Promotion of legislative and policy change will be a crucial step in strengthening immunization policies and extending national immunization programs beyond childhood to include adults and others at risk of vaccine-preventable disease [56]. National immunization technical advisory groups will play a crucial role in making evidence-based immunization recommendations that extend vaccination beyond childhood and are appropriate in national and subnational contexts [56, 57]. Government funding and financial support from partnering with the private sector and foundations will be important for realizing immunization initiatives at country and global levels [56, 57].

Simplifying Vaccination Schedules Through Co-administration and Combination Vaccines

Co-administration and use of combination COVID-19, influenza, and RSV vaccines may be viable strategies to enhance vaccine coverage in at-risk populations. Acceptability of these approaches in the public sphere is generally favorable. In a cross-sectional online survey of Italian adults, most interviewees expressed willingness to receive co-administration and combination influenza and COVID-19 vaccines [58]. Moreover, in a systematic literature review and meta-analysis of 30 studies on combining influenza and COVID-19 vaccines, this approach was identified as an effective strategy to increase uptake by populations reluctant to receive an additional dose of a COVID-19 vaccine [59].

Several countries have implemented policies supporting the co-administration of COVID-19 and seasonal influenza vaccines, including the United States, the United Kingdom, Canada, and all countries of the European Union [60]. Although adoption of policy is less clear, co-administration of the RSV vaccine along other RVI vaccines can also be considered; as the RSV vaccine is new, clinical data on co-administration are limited and safety monitoring is ongoing [61]. Importantly, evidence from clinical trials of co-administration of seasonal influenza and COVID-19 vaccines indicates that this approach has acceptable safety and tolerability profiles, with minimal immunological interference in adult populations [62–64]. In practice, co-administration of seasonal influenza and COVID-19 vaccines is low. In a cross-sectional study of older US Medicare beneficiaries vaccinated against COVID-19, while influenza vaccine uptake was high, co-administration was generally low across two influenza seasons (2021, 11.1%; 2022, 36.5%) [65]. In sub-group analyses, co-administration was less likely among older adults, women, non-whites, and those residing in metropolitan areas [65]. To address the low rates of co-administration, efforts such as expanding vaccine availability, marketing during the influenza season, and promoting vaccine literacy to counter vaccine hesitancy have been suggested [60, 65].

Although less common among adults, the combination vaccine approach is well-established in pediatric immunization programs [66]. The benefits of combination vaccines in this population are numerous and include fewer delays in disease protection; fewer injections, and thus less pain and discomfort; improved adherence to vaccination recommendations and dose schedules; and fewer healthcare appointments and use of resources, resulting in reduced costs, inconvenience, and time away from work or other activities [66].

Collectively, co-administration or combination vaccines are highly effective ways to increase RVI vaccination coverage through reducing the number of vaccination consultations and costs, improving adherence to vaccination recommendations, ensuring timely vaccination according to age or individual needs, and adopting and implementing new vaccines into existing vaccine schedules [67, 68].

Addressing Vaccine Hesitancy

It is essential to identify and assess barriers to vaccine uptake in order to develop efficient strategies to address vaccine hesitancy [69]. In a review of barriers and drivers to routine vaccination in adults aged ≥ 50 years old globally, a recommendation to vaccinate from an HCP was positively correlated with acceptance of vaccination, while a lack of recommendation was negatively correlated [40]. Therefore, vaccination-focused HCP training will be vital to ensure adherence to vaccination recommendations and increase vaccine confidence and uptake [40, 47, 69, 70]. Broadening training to include community leaders can embolden vaccine champions to discuss vaccination in their communities and to help address misinformation, thereby further building vaccine confidence [69]. Pro-vaccine advocacy groups also play a role in decreasing vaccine hesitancy, particularly through countering misinformation distributed online [71].

Consumer education on the risks of RVIs and the benefits of vaccination will be important to increase vaccine acceptance and bring about behavioral change amongst those who are vaccine hesitant [70]. While broad vaccine information campaigns can shape community attitudes toward vaccines, tailored communication is often necessary to reach high-risk or vulnerable populations, including racial and ethnic minority groups [40, 69]. A variety of communication formats have proven effective, including social media, television, videos, leaflets, mailouts, and posters [40, 70].

Using Enhanced Vaccine Platforms to Improve Vaccine Efficacy and Uptake

The mRNA vaccine platform represents a promising alternative to conventional vaccines, providing key advantages such as ease of adaptation to new antigens and swift response to emergence of new viral strains [72, 73]. The scale-up and manufacturing efficiency of the mRNA vaccine platform enables rapid deployment of new vaccines, improving responsiveness to emerging outbreaks [72, 73]. mRNA-based vaccines for SAR-CoV-2 demonstrate that this technology could enable the rapid development of safe and highly effective vaccines readily adaptable to emerging variants of concern [74–76]. Utilizing the mRNA platform for seasonal influenza vaccines could prevent acquired mutations associated with egg- and cell-based platforms, which can limit vaccine effectiveness, and would enable rapid adaptation to virus strain changes, thereby facilitating the deployment of vaccines closely matched to circulating strains [77].

In addition, investigational combination respiratory mRNA vaccines that include COVID-19, influenza, and RSV are being studied [78]. Combination respiratory vaccines are designed for convenience, increased uptake, and higher compliance, with the potential for substantial benefits to healthcare systems [78].

Improved Strategies for Surveillance and Monitoring to Fully Appreciate Disease Burden and Impact of Vaccination

Integrated surveillance systems for RVIs will be crucial to accurately assess RVI disease burden, evaluate the impact of vaccination, and direct resources to where they are needed most [33, 34]. Integrated surveillance systems should provide accurate epidemiological data at both national and regional levels, including RVI incidence by age, place, and level of severity such as hospitalization, admission to intensive care unit, and death; monitor changes and characteristics of circulating respiratory viruses; include genomic monitoring; and, crucially, assess vaccine effectiveness [34]. Successful implementation of integrated RVI surveillance systems will be dependent on overcoming identified barriers such as lack of infrastructure and resources and legislative issues, including a lack of legislative frameworks and adherence to privacy laws [38]. Real-time forecasting models that use epidemiological data from one location and human mobility data to forecast incidence at other locations without surveillance have been proposed to optimize RVI disease surveillance where resources are limited [35]. Additionally, to accurately capture current vaccination rates in at-risk populations, it will be important to ensure that all providers (e.g., pharmacists, general practitioners, and specialists) can contribute to national vaccination registries.

Improving Access to Vaccines

Key strategies to increase RVI vaccine access and uptake include ensuring that RVI vaccination is convenient and removing any financial barriers [40]. Access to vaccinations can be made more convenient by offering them in clinics, pharmacies, workplaces, and other accessible locations at convenient times [40, 56], as well as by offering co-administration of two or more vaccines during the same appointment [68]. Vaccine uptake can also be enhanced by integrating immunization into broader primary healthcare planning and health registers, and optimizing all patient interactions with the healthcare system by verifying vaccination status and offering missed vaccines [56]. Financial barriers to vaccination can be overcome either through provision of publicly funded national immunization programs or health insurance coverage [40].

Conclusions

SARS-CoV-2, influenza virus, and RSV place a substantial burden on vulnerable populations, including older adults and other at-risk populations. Vaccination is crucial for these groups, as herd immunity alone cannot adequately prevent or mitigate severe outcomes. In this article, we have summarized the primary barriers to optimal vaccination coverage and the strategies to overcome such barriers. Combination vaccines against multiple RVIs are of particular interest, providing a streamlined approach to foster adherence to recommendations and increase coverage through simplified vaccination schedules. Future directions in the field include expanding protection against other respiratory viruses by leveraging traditional and novel vaccine platforms to develop new vaccines. The availability of contemporary and updated vaccination strategies for RVIs has created an opportunity to achieve optimal vaccination rates in at-risk populations; however, strategy implementation has lagged behind knowledge and requires more collective efforts from HCPs, policymakers, and the population in general.

Author Contributions

Stefania Maggi, Odile Launay, and Rachel Dawson conceptualized the manuscript, provided oversight and critical evaluation of the content, and approved the submitted version.

Funding

This supplement, and the journal’s Rapid Service Fee, was funded by Moderna, Inc.

Declarations

Conflict of Interest

Stefania Maggi has speaking engagements/honoraria/research grants from: Moderna, Merck, Pfizer, Sanofi, GSK, Janssen, and BioNTech. Rachel Dawson is an employee of Moderna, Inc., and holds stock/stock options in the company. Odile Launay has speaking engagements/honoraria/research grants from: Moderna, Merck, Pfizer, Sanofi, GSK, and Janssen.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.