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DOI: 10.1055/a-2500-2121
Vaccination against Respiratory Infections in the Immunosenescent Older Adult Population: Challenges and Opportunities
Funding None.
- Abstract
- Burden of Respiratory Diseases in Older Adults
- Challenges of Vaccination against Respiratory Diseases in Older Adults
- Opportunities
- Conclusion
- References
Abstract
Respiratory infections are associated with a huge burden of disease every year and disproportionately affect older adults, namely those aged 65 years and older. Older adults are at increased risk of infections compared with their younger counterparts, and once infected, have a higher risk of experiencing severe disease course, complications, and long-term sequelae. Therefore, vaccination is clearly a key strategy to prevent infection and its attendant negative consequences. We review here the burden of common respiratory diseases in older adults, namely influenza, pneumococcal disease, and respiratory syncytial virus. We then review some of the challenges facing immunization of older adults, namely immunosenescence, inflammaging, and low vaccine uptake. Next, potential opportunities for overcoming these challenges are reviewed, including the use of higher antigen doses and/or adjuvants in vaccine formulations for older adults, and the potential of multiomics analyses to improve development, performance, and implementation of vaccines.
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Keywords
respiratory infection - vaccination - influenza - pneumococcal disease - respiratory syncytial virus - older adultsRespiratory infections, caused by viruses (such as influenza, severe acute respiratory syndrome coronavirus 2, or respiratory syncytial virus [RSV]), or bacteria (such as pneumococcus), are associated with a huge burden of disease every year, disproportionately affecting the older members of the population (those aged 65 years and older). Older adults are at increased risk of infection compared with their younger counterparts, and once infected, have a higher risk of experiencing severe disease course, complications, and long-term sequelae.[1] Many older adults also suffer from comorbidities and/or frailty, and severe infection against such a background can compound frailty, accelerate cognitive and physical decline, and ultimately lead to loss of autonomy. Furthermore, the consequences of severe illness in older adults also have implications for the health care system and society as a whole, due to the direct costs associated with hospitalization and treatment, and due to the indirect costs, such as lost productivity of patients and caregivers. Therefore, prevention of infectious respiratory diseases in older adults is of paramount importance to promote healthy aging, maintain autonomy and functionality, and avoid severe illness that could precipitate decline toward frailty, dependency, and, ultimately, death.[1]
Vaccination is undoubtedly the most effective health intervention ever and is estimated to have saved 154 million lives since the World Health Organization (WHO) launched the Expanded Program on Immunization (EPI) in 1974.[2] In that modeling study, each life saved was estimated to correspond to an average of 66 years of full health, corresponding to 10.2 billion years of full health gained.[2] The recent coronavirus disease 2019 (COVID-19) pandemic highlighted the importance of vaccination as a public health measure with the potential to achieve population-scale reductions in disease burden. However, the full benefits of vaccination in older adults are not currently being reaped due to insufficient uptake. Despite the widespread availability of vaccines against the leading vaccine-preventable diseases, notably influenza, pneumococcal disease, and COVID, uptake of vaccination among adults remains low, with a corresponding persisting high burden of disease.[3] The European Center for Disease Prevention and Control reported that in the European Economic Area, coverage rates for seasonal influenza vaccine varied significantly between countries in Europe, ranging from a low of 12% (in Poland and Slovakia) to a high of 78% (in Denmark), with only two countries (Denmark and Ireland [76%]) exceeding the recommended 75% coverage rate in this age category.[4] Similarly, the U.S. Centers for Disease Control and Prevention (CDC) reported that in 2021, coverage with at least one dose of any type of pneumococcal vaccine among adults over 65 years in the United States was 65.8%,[5] whereas in Europe vaccine coverage is reported between 20 and 30%.[6] Clearly, a substantial proportion of the older population remains at risk of respiratory diseases and their attendant consequences. This is of particular concern among older adults suffering from chronic respiratory diseases.[7] We review here the opportunities and challenges associated with vaccination for the prevention of respiratory disease in older adults. A visual summary of the key ideas is presented in [Fig. 1].
Burden of Respiratory Diseases in Older Adults
The burden of respiratory disease in the world is staggering, with acute respiratory infections accounting for approximately 4 million deaths worldwide annually.[8] Older persons are disproportionately affected in terms of both frequency and severity. With the proportion of the world's population aged over 60 years projected to increase 2-fold by 2050, to reach around 22%,[9] the burden of disease will continue to rise unabated. We will review hereafter the burden of influenza, pneumococcal, and RSV infections in older adults.
Influenza
Seasonal influenza is an acute and contagious viral respiratory infection that presents with symptoms such as pyrexia, myalgia, and cough, although in older adults the symptoms might be blunted or absent, and a fall or delirium might be at the onset of the infection.[10] The WHO estimates that there are around one billion cases of seasonal influenza annually, including between 3 and 5 million cases of severe illness, and 290,000 to 650,000 respiratory deaths annually.[11] Mortality from influenza is the highest among older adults (>70 years), according to the Global Burden of Disease Study, accounting for 16.4 deaths per 100,000.[12] A recent epidemiological study from France spanning eight consecutive influenza seasons (2010–2018) reported that 70% of all hospitalizations directly and indirectly related to influenza, and 77% of the associated costs, concerned adults aged over 65, a group that also bore more than 90% of excess influenza-related mortality.[13]
The effects of influenza extend beyond the immediate consequences of the infectious episode and its potential complications. In patients with cardiovascular disease, influenza infection can prompt exacerbation of the underlying condition, notably heart failure and acute ischemic heart disease, for example.[14] [15] There is a bidirectional relationship between cardiovascular disease and influenza, whereby each increases the risk of the other.[14] In a self-controlled case-series study including 364 hospitalizations for acute myocardial infarction that occurred within 1 year before and 1 year after laboratory-confirmed influenza, Kwong et al reported a significantly increased risk of acute myocardial infarction in the risk interval of 7 days after influenza, with an incidence ratio of 6.05 (95% confidence interval [CI], 3.86–9.50).[16]
Vaccination against influenza can effectively mitigate the risk of cardiovascular events by preventing the triggering influenza episode, and there is a large body of evidence in support of this observation.[14] [15] [17] [18] [19] In a meta-analysis of six randomized controlled trials totaling 9,340 patients at high cardiovascular risk, influenza vaccination was shown to be associated with a significant reduction in the incidence of cardiovascular events, cardiovascular death, and all-cause death.[20] In the randomized, controlled IAMI (Influenza Vaccination After Myocardial Infarction) trial, a single dose of influenza vaccine administered within 72 hours after percutaneous coronary intervention or admission for acute coronary syndrome was associated with a significant reduction in the composite endpoint of all-cause death, myocardial infarction, and stent thrombosis, as well as with significant reductions in all-cause and cardiovascular death at 12 months.[21]
The benefits of influenza vaccination in older patients are clearly demonstrated, especially in those with comorbidities, since there are off-target benefits of averting an acute influenza episode, particularly in patients with cardiovascular disease. Vaccination against influenza is safe and effective[22] and is almost universally recommended for older adults by local, regional, and national authorities, and international organizations such as the WHO and CDC.[23] [24] The CDC, the Canadian health authorities, and several countries of the European Union recommend the preferential use of enhanced vaccines, such as high-dose vaccine formulations or adjuvanted vaccines for adults aged over 65 years.[14] [25] [26]
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Pneumococcal Disease
Streptococcus pneumoniae is a ubiquitous pathogen that causes a wide spectrum of invasive and noninvasive diseases. It is an encapsulated bacterium with a polysaccharide capsule, which is a key contributor to its virulence. It is spread by coughing, sneezing, and via respiratory secretions. The most common form of invasive pneumococcal disease (IPD) is pneumococcal pneumonia.[27] Among the various possible etiologies of lower respiratory tract infection, pneumococcal pneumonia accounted for the highest morbidity and mortality worldwide, with approximately 1.18 million deaths and 197 million episodes of disease in 2016 according to the Global Burden of Disease study.[28] As for influenza, the risk of community-acquired pneumococcal pneumonia is particularly high in older adults,[29] a risk that is compounded by the presence of comorbidities and immunosenescence.[30] Pneumococcal community-acquired pneumonia (CAP) has severe consequences for older adults, including hospitalization and increased risk of mortality, with possible downstream repercussions including impaired functional capacity and loss of autonomy.
There are two main types of vaccines available currently: first, the pneumococcal polysaccharide vaccine (PPSV), which comprises a purified preparation of the capsular polysaccharide and includes 23 pneumococcal serotypes; and second, pneumococcal conjugate vaccines (PCV), which combine a bacterial polysaccharide covalently conjugated to a carrier protein with immunogenic potential. Available formulations of the PCV vaccine have evolved from the initial version comprising 7 serotypes, to current versions covering 15 and up to 21 serotypes.[30] [31]
The population-based CAPAMIS cohort study that included over 27,000 adults aged over 60 years in Spain showed that recent (<5 years) vaccination with PPV23 was associated with a significantly reduced risk of overall pneumococcal CAP (hazard ratio [HR], 0.49; 95% CI, 0.29–0.84) and all-cause CAP (HR, 0.75; 95% CI, 0.58–0.98).[32] In the landmark randomized, double-blind, placebo-controlled CAPiTA trial, vaccine efficacy of PCV13 was 75% for the prevention of a first episode of vaccine-type invasive pneumococcal disease among the study population of 84,496 adults aged 65 years or older.[33] Of note, one post hoc analysis from the CAPiTA program estimated PCV13 efficacy at 49.3% (95% CI, 26.2–67.1) in the 65 to 74 year age group and 40.5% (95% CI: 3.3–65.9) in those aged 75 to 84 years, highlighting the important interaction of age with vaccination effectiveness in this context.[34] A meta-analysis by Falkenhorst et al reported significant vaccine efficacy/effectiveness of PPV23 against both IPD and pneumococcal pneumonia by any serotype in older adults and comparable to that of PCV13.[35]
Similar to influenza vaccination, pneumococcal vaccination also yields benefits beyond the target infection. In a systematic review and meta-analysis of 7 observational studies totaling 163,756 adults with a history of, or at a very high risk of cardiovascular disease, Marques Antunes et al reported a significant, 22% reduction in all-cause mortality (HR: 0.78, 95% CI: 0.73–0.83) among those who were vaccinated (PPSV23 and/or PCV13).[36] As underlined by these authors, the deleterious effects of pneumococcal disease in patients with cardiovascular disease are thought to be mediated by activation of the sympathetic system, hypoxemia of the tissues, production of proinflammatory cytokines in response to infection, endothelial dysfunction, and a hypercoagulable state.[36] Patients with heart failure are particularly endangered by pneumococcal disease, as shown in a recent report from the PARADIGM-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) and PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in Heart Failure with Preserved Ejection Fraction) trials, where the incidence of pneumonia was around three times higher patients with heart failure than the expected rate, and a first episode of pneumonia was associated with 4-fold higher mortality.[37]
Based on the body of evidence demonstrating the safety and efficacy of pneumococcal vaccination in older adults, numerous countries recommend pneumococcal vaccination, although the age, recommended vaccine, and reimbursement schedules differ across the European Union.[38] The Advisory Committee on Immunization Practices (ACIP) recommends pneumococcal vaccination for adults aged 65 years and older, advocating a combination of PPSV23 and PCV, with the exact doses and schedules depending on each patient's age, comorbidities, and prior vaccination history, in a shared decision-making approach.[39] Professional societies of cardiology in both Europe and the United States recommend pneumococcal vaccination for patients with heart failure.[40] [41]
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Respiratory Syncytial Virus
Respiratory syncytial virus is a single-stranded RNA virus of the Pneumoviridae family and is a common cause of respiratory infection in both children and adults. The virus features enveloped viral particles containing key surface glycoproteins such as the G protein, which enable the virus to invade host cells. It is transmitted via droplets expulsed during coughing and sneezing. RSV infections follow a marked seasonal pattern that is similar to that of influenza, typically peaking in the winter months in temperate climates, and in the summer months in tropical climates.[42] As with the other respiratory infections detailed above, the burden of RSV infection is particularly high in older adults, with an estimated 1.5 million episodes of RSV-related acute respiratory infection among older adults in 2015 in industrialized countries, of which around 14.5% required hospitalization, and annual mortality is estimated at approximately 14,000 deaths.[43] In the Global Burden of Disease study, RSV infections were the second leading etiology of lower respiratory infection deaths (76,612, 95% uncertainty interval, 55,121–103,503), after pneumococcal pneumonia.[28] As also observed for other respiratory diseases, individual with comorbidities, notably cardiopulmonary disease, are at substantially increased risk of infection.[43] [44] Despite these alarmingly high figures, it is thought that the true incidence and burden may actually be underestimated due to various factors, including insufficient testing due to lack of awareness among health practitioners, absence of specific treatments, and the high cost of diagnostics.[45] [46]
Vaccines against RSV infection have only recently been approved (May 2023) and are gradually being marketed around the world. As a result, epidemiological data about the effectiveness of vaccination in various populations of interest, notably older adults, are still lacking. Existing data stem mainly from the seminal studies that served to underpin the vaccine approval. In a randomized, placebo-controlled, phase 3 trial of the AS01E-adjuvanted RSV prefusion F protein-based vaccine developed by GSK (RSVPreF3 OA, Arexvy) 24,966 adults aged 60 years and over were assigned in a 1:1 ratio to receive a single dose of the vaccine or placebo.[47] After a median follow-up of 6.7 months, vaccine efficacy against polymerase chain reaction-confirmed RSV-related lower respiratory tract disease was 82.6% (96.95% CI, 57.9–94.1), 94.1% (95% CI, 62.4–99.9) against severe RSV-related lower respiratory tract disease (based on clinical assessment by investigators), and 71.7% (95% CI, 56.2–82.3) against RSV-related acute respiratory infection.[47] Importantly, efficacy exceeded 80% in adults aged 60 to 79 years. Efficacy against RSV-related lower respiratory tract disease was 56.1% in the second season.[48]
A double-blind, placebo-controlled phase 3 clinical trial tested the efficacy of the RSVpreF vaccine developed by Pfizer (Abrysvo), among 36,862 adulted aged ≥ 60 years, randomized in a 1:1 ratio to a single dose of either vaccine or placebo.[49] Vaccine efficacy against RSV-associated lower respiratory tract illness with three or more symptoms was 88.9% in the first season.[49]
The pivotal phase III study for the Moderna mRNA vaccine was conducted in 35,541 adults aged 60 years or older, and efficacy against RSV-associated lower respiratory tract disease with at least 3 signs or symptoms was 82.4% (96.36% CI, 34.8–95.3).[50]
Based on the available evidence, the ACIP recommends a single dose of any RSV vaccine adults aged ≥ 60 years.[51] Few countries in the European Union have official recommendations in place as yet, but this is likely to change in the coming months with the ongoing emergence of new data.[52]
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Challenges of Vaccination against Respiratory Diseases in Older Adults
Immunosenescence
One of the major challenges of vaccination is that older adults mount a less robust response to immunization with increasing age, resulting in reduced protection. The age-related decline in immunity observed in older adults, a phenomenon termed immunosenescence, is the cumulative effect of a wide range of mechanisms affecting various cell types (within the innate and adaptive immune system, but also in the gut microbiota) across multiple signaling pathways, biological networks, and tissue types. Involution of the primary lymphoid organs, primarily the thymus and bone marrow, is associated with decreased levels of B- and T-cell progenitors, lower production of antibodies, accumulation of dysfunctional memory cells, and increased production of proinflammatory cytokines.[53] [54] The innate immune response at the injection site can become less reactive. In particular, neutrophils in older adults show reduced chemotaxis,[55] with failure to correctly initiate recruitment of other immune cell types, failure to activate appropriate signaling pathways, and dysregulation of cytokine production. Dendritic cells, whose role is antigen recognition, uptake, and presentation, lose functionality with increasing age, which may stifle T-cell response.[53] Further, the T-cell compartment undergoes profound alterations, with declining frequency of naïve T-cells and greater predominance of antigen-experienced T-cells, which are less responsive to stimulation by antigens.[1] In parallel, B-cells may become defective, and combined with the declining functional response of memory and effector T-cells, the overall result is a less effective response to vaccination, with a lower quantity, quality, and durability of antibodies.[53] [54] [56] Overall, the cumulation of various deficits across both the innate and adaptive immune system is a multifactorial process that significantly hampers the capacity to mount a coordinated and effective immune response and negatively affects the protection yielded by vaccination, leaving many older adults at increased risk of infection, severe disease course, and complications. Immunosenescence is also related to frailty and the current evidence suggests that infections and frailty repeatedly cross each other's pathophysiological paths, accelerating the aging process in a vicious circle. Such evidence suggests that the maintenance of a well-functioning immune system may be accomplished by preventing frailty, and vice versa, and that increasing adherence to immunization may delay the onset of frailty and maintain immune system homeostasis, beyond preventing infections.[57]
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Inflammaging
Inflammaging is a term first coined by Claudio Franceschi and coworkers to characterize a state of chronic, low-grade inflammation, and it has now become recognized as a hallmark of aging.[58] Inflammation is a natural, necessary, physiological reaction whose primary purpose is to respond to transient injury, and to promote recovery and repair, and is beneficial to the body in this scenario. However, persistent inflammation has deleterious effects that can contribute to reducing the ability to mount an effective response to vaccination. Inflammaging is multifactorial in origin and includes contributing factors such as damage to a wide range of cell and tissue types, reduced clearance of dysfunctional and/or senescent cells, and dysbiosis of the gut microbiota. Indeed, age-related changes to the gut microbiota may lead to intestinal permeability and leakage of proinflammatory substances into the circulation, promoting systemic inflammation.[54]
Another term coined by Franceschi and colleagues is immunobiography, which postulates that a lifetime's exposure to internal and external immunological stimuli, mediated by the epigenetic and genetic backdrop, result in a wide spectrum of immunological phenotypes.[59] Consequently, in this lifespan perspective, there is a corresponding high interindividual variability in responsiveness of the immune system. In this regard, immunobiography reflects individual profiles of the speed of aging, characterized by the gap between biological and chronological age. One key, nonmodifiable contributor to this process is sex, and while the longer life expectancy of females has long been noted, there is also a clear trend for older women to have lower susceptibility to infection and a better response to immunization, thought to be related to the impact of sex hormones on immunity.[54] [60] Since it takes a lifetime of exposures and immunological experiences to shape each individual's immunological profile, it seems utopic to imagine that targeting one specific aspect of the immune response could overcome the system-level decline in immune responsiveness. Therefore, taking immunobiography into account at a systems level could help to inform the design of new therapeutics or vaccines to improve vaccine response in older individuals.
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Correlates of Protection
Since the overarching aim of vaccination is to induce immunity against the targeted pathogen, a key issue in establishing the efficacy of vaccination is choosing the appropriate marker of protection. In general, serum antibody titers are used to reflect vaccine response. For influenza, the hemagglutinin antibodies are used as the surrogate for protection, although in older adults, for influenza, T-cell-mediated response has been purported to be a better reflection of protection.[53] [61] Indeed, hemagglutinin assays do not account for age-related decline in cell-mediated immune response, and thus, immune response to vaccines in older adults should be based on both humoral- and cell-mediated processes to accurately assess overall protection.[62] Additionally, high titers of hemagglutinin antibodies do not necessarily confer optimal protection, whereas low titers do not necessarily translate into increased susceptibility.[63] [64] With the influenza virus, there is also the problem of mismatch between the strains included in the vaccine, and the circulating strains during the peak influenza season. Influenza vaccine efficacy may also wane within a single season in older adults, leaving them susceptible to infection toward the end of the season.[1] In addition, cross-protection from previous influenza infection and/or vaccines received in prior seasons may affect the level of protection. With pneumococcal vaccines, antibody response is measured using enzyme-linked immunosorbent assay (ELISA). With the multiplicity of different serotypes, different antibody levels against each serotype correspond to varying degrees of protection. Consequently, the true efficacy of pneumococcal vaccines may diverge, depending on the epidemiology and composition of serotypes.[64] For the recently approved RSV vaccines, the seminal studies assessed immunogenicity via an RSVPreF3-specific IgG ELISA, and RSV A and B neutralization assays, calculating the geometric mean increase in antibody titers,[47] or measurement of RSV-F–specific T-cell responses using an interferon-γ ELISA.[49] In practical terms, the rates of laboratory-confirmed infection and/or hospitalization for the target illness are most widely used as outcomes in clinical trials testing the effectiveness of vaccines. The various biological correlates of protection may be affected by immunosenescence, with most vaccines in any case eliciting a lesser immune response in older persons than in younger adults.[54] [65] A recent stakeholder workshop identified areas for improvement with a view to accelerating and improving vaccine development, including standardization of sample collection, assay choice, and data analysis; further research is warranted into mucosal immune responses, how this phenomenon can best be measured, and how it relates to vaccine effectiveness, and a need for enhanced understanding of how cell-mediated responses contribute to protective immunity.[66]
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Low Vaccine Uptake
There is a substantial body of literature attesting to the fact that uptake of vaccines is suboptimal.[67] [68] For example, in the United States, the CDC estimated that influenza vaccine coverage was 69.7% in the 2023 to 2024 season among adults aged 65 years and older, a similar rate to that estimated for 2022 to 2023.[69]
Vaccine uptake is influenced by a wide range of factors, including sociodemographic, financial, cultural, and societal characteristics.[70] [71] Low coverage rates mean that substantial proportions of at-risk individuals remain susceptible to infection as well as adversely affecting the herd immunity phenomenon. Various strategies have been employed to increase uptake of age- and health status-appropriate vaccines,[72] including electronically delivered nudges to improve uptake of influenza vaccination,[73] an inexpensive and easy-to-implement strategy. In the wake of the COVID-19 pandemic, and the intense media attention focused on vaccine development and deployment, there has been some concern that vaccine fatigue may set in, namely a feeling of inertia or inaction toward vaccine information and vaccination, due to perceived overburden and burnout.[74] If this phenomenon were to spill over into other vaccine behaviors, notably by reducing uptake of seasonal influenza vaccine or pneumococcal vaccines, this could represent a serious threat to public health, given the already striking burden of these diseases among older adults. Against this background, targeted interventions to increase vaccine uptake, particularly among high-risk groups such as older adults, are warranted and should be designed with the structural and nonstructural barriers specific to each sociodemographic group in mind.[75] In this regard, in Europe a major commitment is provided by the Adult Immunization Board (AIB), created with the primary goal to provide evidence-based guidance on fundamental technical and strategic issues, while monitoring the progress of adult immunization programs at the European and national levels.[76]
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Opportunities
Enhancing Immunogenicity of Vaccines for Older Adults with Higher Antigen Doses
One strategy to overcome the reduced response to vaccination observed in older adults is to increase the dose of antigen. Formulations of the influenza vaccine have been developed that contain higher antigen doses, namely a 4-fold increase, from 15 to 60 µg of hemagglutinin. The increased volume of antigen available allows for greater uptake by dendritic cells for presentation to lymphocytes, leading to an enhanced response to the vaccine, in terms of immunogenicity and immunological protection.[1] [77] A meta-analysis of five randomized trials testing high-dose versus standard-dose influenza vaccine and totalling over 100,000 adults aged over 65 years, reported that high-dose vaccination had a relative vaccine effectiveness (rVE) of 23.5% (95% CI, 12.3–33.2%) in preventing hospitalization for pneumonia and influenza, and 7.3% (95%CI, 4.5–10%) in preventing all-cause hospitalization.[78] Elsewhere, a larger meta-analysis of randomized and observational studies evaluated the rVE of high-dose versus standard-dose influenza vaccine against influenza-related outcomes in adults aged over 65 years, in a total of over 45 million persons spanning 12 influenza seasons.[79] The results showed that high-dose vaccination provided significantly better protection, not only against the influenza-related outcomes of interest (namely influenza-like illness and influenza-related hospitalizations) but also against other outcomes, such as cardiovascular, respiratory, and all-cause hospitalizations.[79]
The U.S. ACIP recommends that older adults (>65 years) received high-dose or adjuvanted influenza vaccines.[25]
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Enhancing Immunogenicity of Vaccines for Older Adults Using Adjuvants
A second strategy employed to overcome lower immune response in older adults is the use of adjuvants, that is, substances that boost the immunogenicity of vaccine formulations when administered concomitantly with the antigen.[80] The adjuvant can help to accelerate the onset and augment the magnitude of immune response and may also provide cross-protection in older adults, for example.[54] Most vaccine adjuvants act as immunostimulants, namely they are heralded as a danger signal by the organism, prompting activation of the various cells in the immune system that are responsible for antigen presentation, and initiation of pattern recognition receptor signaling pathways that stimulate immune response. Other adjuvants merely act as more efficient vehicles for transferring a higher antigen load or targeting its delivery to a more specific site or cell type or by mimicking the form and shape of pathogens [for a comprehensive review of vaccine adjuvants, see].[81] For many years, aluminum salts were the only adjuvant used in vaccines, but technology has now progressed rapidly, and a wide range of new substances are currently employed as adjuvants, including nanoparticles, synthetic molecules, emulsions, and extracts of naturally occurring substances, such as squalene, and more recently, lipid nanoparticles as used in COVID vaccines.
The adjuvants MF59 and AS03 are currently used in influenza vaccines specifically destined for older adults. MF59 is an oil-in-water emulsion containing the naturally occurring molecule squalene. Squalene is produced and present in the human body but is most abundant in shark liver. MF59 is well established as a safe and potent vaccine adjuvant and is used in the FLUAD influenza vaccine to boost the immune reaction by enhancing cell recruitment to the injection site via production of chemokines and interleukin. MF59 also exacerbates B-cell response, thereby enhancing the quantity and quality of antibody production.[53] MF59 also produces a wider spectrum of immune response, affording protection against heterologous strains of influenza virus, for example.[82] AS03 is an oil-in-water emulsion containing α-tocopherol and squalene, with similar adjuvant properties to MF59. It enhances antibody and T-cell responses to hemagglutinin and was shown to have an acceptable safety profile based on data from clinical trials totaling over 55,000 vaccinated subjects and postlicensure data from approximately 90 million administered doses AS03-adjuvanted influenza vaccines.[83] In a large randomized trial in adults aged over 65 years, AS03-adjuvanted trivalent influenza vaccine was shown to elicit a strong antibody response 3 weeks after vaccination, with persistence of antibodies at 6 months.[62] One of its main advantages over other emulsions is that it requires a lower dose of antigen to elicit a strong humoral immune response (i.e., approximately half the amount of antigen per strain compared with other conventional trivalent inactivated influenza vaccines).[84] Finally, AS01E, another member of the proprietary Adjuvant System family, is an oil-in-water emulsion that is licensed for use as an adjuvant in the RSV vaccine. It is a liposome-based system that contains two immunostimulants, namely 3-O-desacyl-4ʹ-monophosphoryl lipid A and the saponin QS-21. It has been shown to efficiently promote CD4+ T-cell-mediated immune response.[85]
Recent years have seen major advances in the field of vaccine adjuvants, and numerous candidate adjuvants are under development or currently being tested. Future perspectives in adjuvant research include the replacement of naturally occurring substances by synthetic substitutes, which could enable larger-scale production at lower cost, with greater biological stability and lesser dependence on supply chains or resource availability for substances that have to be sourced in nature. Other avenues for research could target the wide biological diversity of vaccine recipients, reflecting the immunobiological profiles mentioned above. Safety evaluations also need to take into account the proinflammatory pathways stimulated by vaccine adjuvants in older patients who may already have underlying chronic, low-grade inflammation (inflammaging).
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Systems Vaccinology, Omics Analyses, and Artificial Intelligence
The unlimited power of artificial intelligence offers immense perspectives for high-throughput analysis of the myriad factors that contribute to immune response, ranging from the genetic and epigenetic environments, to individual sociodemographic, clinical, immunological, and immunobiographical profiles, to the many signaling pathways and molecular substances that interact to mount a protective immune response, to predict response to vaccination, identify new correlates of protection, identify targets amenable to enhancement, and improve vaccine design and implementation.[86] In this perspective, systems vaccinology has developed as a field that can apply multiomics technologies to study vaccines and holds the potential to integrate and distil available data with a view to guiding the design of vaccines specifically tailored for older adults. Given the complexity of the biological processes at work in immunization, the multidimensionality requires the power of artificial intelligence solutions, machine learning, and multiomics analyses to find potential “needles” in the ever-expanding “haystack” of data.
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Conclusion
The burden of respiratory diseases in older adults remains staggering and looks set to increase with population aging and increased longevity. Older adults are at higher risk of infection, and once infected, have a higher risk of severe disease course, complications, and sequelae. There is thus a compelling rationale to prevent infectious respiratory diseases through vaccination. Safe and effective vaccines exist for the major infectious respiratory diseases affecting older adults, namely influenza, pneumococcal disease, and RSV. Low uptake in at-risk populations, such as low pneumococcal, influenza, and other respiratory tract infections' vaccination rates in older adults, need to be redressed to prevent not only the target infections, but also the exacerbations of underlying pathologies that may result from an acute episode of severe illness. One of the key challenges facing vaccination of older adults is the age-related decline in immunity known as immunosenescence. Future research in vaccinology should focus on how to stimulate a stronger immune response in older adults, albeit without exacerbating underlying inflammation to harmful levels, as many older adults suffer from chronic, persistent low-grade inflammation. Other perspectives include adjuvant technologies and systems vaccinology, as ways to enhance uptake and immunogenicity of vaccines in older adults, achieving higher levels of protection, thereby preventing infectious respiratory disease episodes, and enabling more and more older adults to experience healthy aging.
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Conflict of Interest
None declared.
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- 21 Fröbert O, Götberg M, Erlinge D. et al. Influenza vaccination after myocardial infarction: a randomized, double-blind, placebo-controlled, multicenter trial. Circulation 2021; 144 (18) 1476-1484
- 22 Demurtas J, Celotto S, Beaudart C. et al. The efficacy and safety of influenza vaccination in older people: an umbrella review of evidence from meta-analyses of both observational and randomized controlled studies. Ageing Res Rev 2020; 62: 101118
- 23 Morales KF, Brown DW, Dumolard L. et al. Seasonal influenza vaccination policies in the 194 WHO Member States: the evolution of global influenza pandemic preparedness and the challenge of sustaining equitable vaccine access. Vaccine X 2021; 8: 100097
- 24 Ortiz JR, Perut M, Dumolard L. et al. A global review of national influenza immunization policies: analysis of the 2014 WHO/UNICEF Joint Reporting Form on immunization. Vaccine 2016; 34 (45) 5400-5405
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- 28 GBD 2016 Lower Respiratory Infections Collaborators. Estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory infections in 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Infect Dis 2018; 18 (11) 1191-1210
- 29 Grant LR, Meche A, McGrath L. et al. Risk of pneumococcal disease in US adults by age and risk profile. Open Forum Infect Dis 2023; 10 (05) ofad192
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Publication History
Accepted Manuscript online:
11 December 2024
Article published online:
30 January 2025
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- 26 Public Health Agency of Canada. Influenza vaccines. Canadian Immunization Guide. Ottawa (ON): Government of Canada; 2023. . Accessed March 17, 2024 at: https://wwwcanadaca/en/public-health/services/canadian-immunization-guidehtml
- 27 Al-Jabri M, Rosero C, Saade EA. Vaccine-preventable diseases in older adults. Infect Dis Clin North Am 2023; 37 (01) 103-121
- 28 GBD 2016 Lower Respiratory Infections Collaborators. Estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory infections in 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Infect Dis 2018; 18 (11) 1191-1210
- 29 Grant LR, Meche A, McGrath L. et al. Risk of pneumococcal disease in US adults by age and risk profile. Open Forum Infect Dis 2023; 10 (05) ofad192
- 30 Elias C, Nunes MC, Saadatian-Elahi M. Epidemiology of community-acquired pneumonia caused by Streptococcus pneumoniae in older adults: a narrative review. Curr Opin Infect Dis 2024; 37 (02) 144-153
- 31 Scott P, Haranaka M, Choi JH. et al; STRIDE-6 study group. A phase 3 clinical study to evaluate the safety, tolerability, and immunogenicity of V116 in pneumococcal vaccine-experienced adults 50 years of age or older (Stride-6). Clin Infect Dis 2024; ciae383
- 32 Ochoa-Gondar O, Vila-Corcoles A, Rodriguez-Blanco T. et al. Effectiveness of the 23-valent pneumococcal polysaccharide vaccine against community-acquired pneumonia in the general population aged ≥ 60 years: 3 years of follow-up in the CAPAMIS study. Clin Infect Dis 2014; 58 (07) 909-917
- 33 Bonten MJ, Huijts SM, Bolkenbaas M. et al. Polysaccharide conjugate vaccine against pneumococcal pneumonia in adults. N Engl J Med 2015; 372 (12) 1114-1125
- 34 van Werkhoven CH, Huijts SM, Bolkenbaas M, Grobbee DE, Bonten MJ. The impact of age on the efficacy of 13-valent pneumococcal conjugate vaccine in elderly. Clin Infect Dis 2015; 61 (12) 1835-1838
- 35 Falkenhorst G, Remschmidt C, Harder T, Hummers-Pradier E, Wichmann O, Bogdan C. Effectiveness of the 23-valent pneumococcal polysaccharide vaccine (PPV23) against pneumococcal disease in the elderly: systematic review and meta-analysis. PLoS One 2017; 12 (01) e0169368
- 36 Marques Antunes M, Duarte GS, Brito D. et al. Pneumococcal vaccination in adults at very high risk or with established cardiovascular disease: systematic review and meta-analysis. Eur Heart J Qual Care Clin Outcomes 2021; 7 (01) 97-106
- 37 Shen L, Jhund PS, Anand IS. et al. Incidence and outcomes of pneumonia in patients with heart failure. J Am Coll Cardiol 2021; 77 (16) 1961-1973
- 38 European Centre for Disease Prevention and Control. Vaccine scheduler: pneumococcal disease: recommended vaccinations. Stockholm: ECDC; 2024. . Accessed August 4, 2024 at: https://vaccine-schedule.ecdc.europa.eu/Scheduler/ByDisease?SelectedDiseaseId=25&SelectedCountryIdByDisease=-1
- 39 Kobayashi M, Pilishvili T, Farrar JL. et al. Pneumococcal vaccine for adults aged ≥19 years: recommendations of the Advisory Committee on Immunization Practices, United States, 2023. MMWR Recomm Rep 2023; 72 (03) 1-39
- 40 McDonagh TA, Metra M, Adamo M. et al; ESC Scientific Document Group. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021; 42 (36) 3599-3726
- 41 Heidenreich PA, Bozkurt B, Aguilar D. et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol 2022; 79 (17) e263-e421
- 42 Li Y, Reeves RM, Wang X. et al; RSV Global Epidemiology Network, RESCEU investigators. Global patterns in monthly activity of influenza virus, respiratory syncytial virus, parainfluenza virus, and metapneumovirus: a systematic analysis. Lancet Glob Health 2019; 7 (08) e1031-e1045
- 43 Shi T, Denouel A, Tietjen AK. et al; RESCEU Investigators. Global disease burden estimates of respiratory syncytial virus-associated acute respiratory infection in older adults in 2015: a systematic review and meta-analysis. J Infect Dis 2020; 222 (Suppl. 07) S577-S583
- 44 Kujawski SA, Whitaker M, Ritchey MD. et al. Rates of respiratory syncytial virus (RSV)-associated hospitalization among adults with congestive heart failure-United States, 2015-2017. PLoS One 2022; 17 (03) e0264890
- 45 Li Y, Kulkarni D, Begier E. et al. Adjusting for case under-ascertainment in estimating RSV hospitalisation burden of older adults in high-income countries: a systematic review and modelling study. Infect Dis Ther 2023; 12 (04) 1137-1149
- 46 Kenmoe S, Nair H. The disease burden of respiratory syncytial virus in older adults. Curr Opin Infect Dis 2024; 37 (02) 129-136
- 47 Papi A, Ison MG, Langley JM. et al; AReSVi-006 Study Group. Respiratory syncytial virus prefusion F protein vaccine in older adults. N Engl J Med 2023; 388 (07) 595-608
- 48 Ison MG, Papi A, Athan E. et al; AReSVi-006 Study Group. Efficacy and safety of respiratory syncytial virus (RSV) prefusion f protein vaccine (RSVPreF3 OA) in older adults over 2 RSV seasons. Clin Infect Dis 2024; 78 (06) 1732-1744
- 49 Walsh EE, Pérez Marc G, Zareba AM. et al; RENOIR Clinical Trial Group. Efficacy and safety of a bivalent RSV prefusion F vaccine in older adults. N Engl J Med 2023; 388 (16) 1465-1477
- 50 Wilson E, Goswami J, Baqui AH. et al; ConquerRSV Study Group. Efficacy and safety of an mRNA-based RSV PreF vaccine in older adults. N Engl J Med 2023; 389 (24) 2233-2244
- 51 Melgar M, Britton A, Roper LE. et al. Use of respiratory syncytial virus vaccines in older adults: recommendations of the Advisory Committee on Immunization Practices - United States, 2023. MMWR Morb Mortal Wkly Rep 2023; 72 (29) 793-801
- 52 European Centre for Disease Prevention and Control. Vaccine scheduler: RSV: Recommended vaccinations. Stockholm: ECDC; 2024. . Accessed August 4, 2024 at: https://vaccine-schedule.ecdc.europa.eu/Scheduler/ByDisease?SelectedDiseaseId=53&SelectedCountryIdByDisease=-1
- 53 Cadar AN, Martin DE, Bartley JM. Targeting the hallmarks of aging to improve influenza vaccine responses in older adults. Immun Ageing 2023; 20 (01) 23
- 54 Ciabattini A, Nardini C, Santoro F, Garagnani P, Franceschi C, Medaglini D. Vaccination in the elderly: the challenge of immune changes with aging. Semin Immunol 2018; 40: 83-94
- 55 Simmons SR, Tchalla EYI, Bhalla M, Bou Ghanem EN. The age-driven decline in neutrophil function contributes to the reduced efficacy of the pneumococcal conjugate vaccine in old hosts. Front Cell Infect Microbiol 2022; 12: 849224
- 56 Frasca D, Blomberg BB. Aging induces B cell defects and decreased antibody responses to influenza infection and vaccination. Immun Ageing 2020; 17 (01) 37
- 57 Vetrano DL, Triolo F, Maggi S. et al. Fostering healthy aging: the interdependency of infections, immunity and frailty. Ageing Res Rev 2021; 69: 101351
- 58 Franceschi C, Bonafè M, Valensin S. et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci 2000; 908: 244-254
- 59 Franceschi C, Salvioli S, Garagnani P, de Eguileor M, Monti D, Capri M. Immunobiography and the heterogeneity of immune responses in the elderly: a focus on inflammaging and trained immunity. Front Immunol 2017; 8: 982
- 60 Fish EN. The X-files in immunity: sex-based differences predispose immune responses. Nat Rev Immunol 2008; 8 (09) 737-744
- 61 McElhaney JE, Xie D, Hager WD. et al. T cell responses are better correlates of vaccine protection in the elderly. J Immunol 2006; 176 (10) 6333-6339
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