If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Infectious Diseases Division, The Miriam Hospital and Rhode Island Hospital, Warren Alpert Medical School of Brown University, Rhode Island Hospital, 593 Eddy Street, POB, 3rd Floor, Suite 328/330, Providence, RI 02903, USA
Case Western Reserve University, School of Medicine, 10900 Euclid Ave, BRB 1025, Cleveland, OH 44106-4984, USAGeriatric Research, Education and Clinical Center, Cleveland Veterans Affairs Medical Center, 10900 Euclid Ave, BRB 1025, Cleveland, OH 44106-4984, USA
Older adults have a higher incidence of hospitalizations and death compared with younger populations. Older adults, especially those with comorbidities, are specifically prone to having the severe disease when infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19.
Coronavirus Disease 2019 (COVID-19) Outbreak Associated With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) P.1 Lineage in a Long-Term Care Home After Implementation of a Vaccination Program—Ontario, Canada, April–May 2021.
Whether this is due to inadequate vaccine coverage or vaccine ineffectiveness is unclear. Vaccination remains the most feasible and easily accessible preventive measure used for protection against COVID-19 among older adults. Thus, there is a significant need to optimize current vaccination measures to protect these populations against COVID-19.
Immune changes in older adults: clinical implications for vaccination
Older adults generate suboptimal immune responses to virtually all vaccines when compared with the younger adult population.
Immunosenescence and inflammaging are two established phenomena associated with the suboptimal immunogenicity of vaccines in older adults. In immunosenescence, the aging immune system is plagued with a progressive functional decline, which reduces its ability to mount an adequate response to new or previously encountered antigens in the form of vaccines or infections.
This decline in cellular and humoral immunity is marked by reduced production of naive B and T cells, an increase in dysfunctional memory cells, and the involution of primary lymphoid organs such as the thymus.
Furthermore, a characteristic reduction in the production of lymphocytes (lymphopoiesis) results in the impairment of the adaptive and innate immune response,
Changes within the bone marrow, such as myelofibrosis, result in the production of short-lived and apoptosis-prone immune cells, with a shift toward myeloid precursor cells.
These cumulative changes create “immune system fatigue” and dampen the ability of the immune system in older adults to be appropriately stimulated by neoantigens and previously encountered antigens alike.
Inflammaging is a progressive state of chronic, sterile low-grade inflammation that contributes to developing disease conditions associated with aging.
Inflammaging is characterized by increased production of proinflammatory cytokines (such as interleukin [IL]-1, IL-6, and tumor necrosis factor [TNF] α) with an increase in the ratio of Th17 cells, a proinflammatory subset of CD4+ T cells, to regulatory T cells. There is also the production of highly inflammatory late memory B cells with reduced telomerase activity, and reduced neutrophilic, monocytic, and dendritic cell functions such as chemotaxis, phagocytosis, signaling pathways, and intracellular killing via free radical production.
As a result, inflammaging causes impairment in B cell function, and it has been reported that these systemically abundant proinflammatory cytokines tend to prevent optimal response to vaccines.
This propensity toward a heightened anti-inflammatory response to low-grade chronic inflammation and suppression of acute inflammatory processes has clinical implications in the form of reduced reactions to vaccines observed in older adults.
Frailty further contributes to the severity of complications suffered from disease and infections. This multifactorial syndrome is marked by a decline in physiologic function and increased susceptibility to environmental stressors,
The Frailty Index, an objective measure of frailty using key clinical and laboratory markers is often used to assess overall health status and risk stratification for serious disease complications among older adults.
Generally, frailty is associated with aging and thus, predominantly occurs among older adults. Notably, a higher degree of frailty is associated with immune function decline, and consequently, the inability to mount an appropriate response to antigenic stimulation by either an infection or vaccine.
These resultant effects of aging on the immune system have diverse ramifications on response to vaccination among this age group. Consequences such as the ability of antigens from vaccines and infections to elicit an appropriate immune response (immunogenicity) and side effects of vaccines (reactogenicity) among these subjects differ from other age groups. These immunologic realities in this age group demonstrate the critical need for studies to best deploy available vaccines and/or engineer better ones.
Immune correlates of protection. Antibodies generally confer protection against infections, and specific antibody levels are often correlated with protection from such infections. Having an immune correlate of protection is very helpful for vaccine development and approval, allowing more rapid and less costly approvals for new vaccines or variations on current vaccines. Although specific correlates of protection from SARS-CoV-2 infection are yet to be established,
seroprotective levels of neutralizing and non-neutralizing antibodies are widely accepted as surrogates for protection in other viruses such as varicella zoster and hepatitis B virus.
The discordance between immunogenicity and efficacy findings for older adults often observed in COVID-19 vaccine trials underscores the difficulty in defining specific immunologic correlates of clinical protection. Emerging variant strains pose an additional challenge because immune correlate may vary depending on the variant. All this taken together suggests that a well-defined immune correlate of protection across age and strain might not exist for COVID-19 vaccines.
Efficacy of current coronavirus disease 2019 vaccines among older adults
The rapid development of COVID-19 vaccines has helped mitigate the pandemic’s devastating effects across all eligible age groups, especially among vulnerable groups including older adults. The World Health Organization (WHO) registry contains more than 300 vaccines in development at different phases of clinical trials of which 11 have been approved for emergency use worldwide.
These approved vaccines use different technologies (Fig. 1); they include the novel messenger RNA (mRNA) vaccines (Pfizer–BioNTech’s Comirnaty BNT162b2 and Moderna’s Spikevax mRNA-1273) and the non-mRNA vaccines such as adenovirus vector-based vaccines (Johnson & Johnson–Janssen’s Jcovden Ad26.COV2.S, CanSino’s Convidecia AD5-nCOV, and AstraZeneca’s Covishield and Vaxzevria AZD1222; ChAdOx1), adjuvanted protein vaccines (Novavax’s Covovax and Nuvaxovid NVX-CoV2373), and inactivated virus vaccines (Sinopharm’s Covilo, Sinovac’s CoronaVac, and Bharat Biotech’s Covaxin). These vaccines and the recently approved bivalent boosters have varying acceptance and usage in different parts of the world but have all remained effective in reducing morbidity and mortality among older adults, as well as other populations.
Effectiveness of the Pfizer-BioNTech and Oxford-AstraZeneca vaccines on covid-19 related symptoms, hospital admissions, and mortality in older adults in England: test negative case-control study.
Fig. 1COVID-19 vaccines according to technologies employed. All are WHO-approved except the viral vector sputnik V vaccine. mRNA, Messenger Ribonucleic Acid; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2; J&J, Johnson and Johnson.
As is typical of vaccine development, initial safety and immunogenicity studies of many of these vaccines focused on middle-aged adults with much less older adult representation. The phase 3 approval trials, however, had better older adult representation with about 25% to 40% of subjects in an older age group category from greater than 55, 60, 65, or 70 years depending on the study (Table 1). This is a reasonable representation in the phase 3 trials. Results from these trials show that most COVID-19 vaccines did not have a significant initial difference in efficacy across the adult age spectrum (see Table 1). This observation suggests independence of vaccine efficacy (VE) from age as it applies to the COVID-19 vaccines in use. Rather than age, frailty may be a better predictor of the efficacy of certain COVID-19 vaccines.
As explained earlier, immunosenescence has implications for the durability of vaccine-induced antibodies in older adults. Consequently, age and frailty are negatively associated with the durability of antibodies postvaccination, whereas a prior infection with SARS-CoV-2 increases durability regardless of age and frailty.
Characteristics associated with serological COVID-19 vaccine response and durability in an older population with significant comorbidity: the Danish Nationwide ENFORCE Study.
Significant Reduction in Vaccine-Induced Antibody Levels and Neutralization Activity Among Healthcare Workers and Nursing Home Residents 6 Months Following Coronavirus Disease 2019 BNT162b2 mRNA Vaccination.
However, this initial reduction in immunogenicity does not necessarily translate into reduced protection for this population because exact immune correlates of protection are yet to be defined. More so, both real-world and trial-reported VE among these older adult populations compares impressively with those reported among other age groups further downplaying the effect of the disparity in observed immunogenicity. Although females have been reported to generate better immune responses to vaccines in general,
Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia.
Impact of age, ethnicity, sex and prior infection status on immunogenicity following a single dose of the BNT162b2 MRNA COVID-19 vaccine: Real-world evidence from healthcare workers, Israel, December 2020 to January 2021.
Of note, the authors caution that a head-to-head comparison of vaccine trials is not ideal due to variables, such as differences in trial settings and participants, symptomatic illness criteria, and predominant variants at the time trials were conducted.
Effectiveness and Immunogenicity of the mRNA Vaccines in Older Adults
The mRNA vaccines, such as those manufactured by Pfizer (BNT162b2) and Moderna (mRNA-1273), were the earliest vaccines approved for emergency use in the United States and are the most widely used vaccines, especially in developed countries with cost, transport, and storage logistics being a major factor limiting their use in developing countries.
The BNT162b2 mRNA vaccine is a lipid nanoparticle-formulated, nucleoside-modified RNA vaccine that encodes a membrane-anchored SARS-CoV-2 full-length spike, stabilized in the prefusion conformation.
This vaccine is administered in a 2-dose regimen 21 days apart. The early phase 2 trial that included 45 healthy adults aged 65 to 85 years reported a decline in immunogenicity with increasing age; however, this response exceeded that of convalescent subjects suggesting the superiority of vaccine-induced immunity over that of natural infection among this age group.
Phase 3 trials reported an overall efficacy of 95.0% (90.0–97.9) after a median follow-up of 2 months with subgroup analysis revealing a consistent but slightly lower VE of 93.7% (80.6–98.8) among adults older than 55 years, 94.7% (66.7–99.9) among adults older than 65 years, and 100.0% (−13.1–100.0) in adults older than 75 years.
The lower immunogenicity trend of the BNT1652b2 primary series observed among older adults seems to be reversed with the booster doses where they were reported to have mounted better responses.
Phase 1 trial of the third dose of the Pfizer vaccine showed a better neutralization capacity in older adults compared with younger adults. Evaluating twelve 65- to 85-year-old participants over 1 month, the geometric mean ratio of neutralizing antibodies was consistently higher between the second and third dose for these older adults than their younger counterparts, underlining the efficacy of an additional dose in this population of older adults.
The mRNA-1273 vaccine is a lipid nanoparticle-encapsulated mRNA-based vaccine that encodes the prefusion-stabilized full-length spike protein of the SARS-CoV-2 virus; it is administered in 2 doses, 28 days apart. A phase 2 open-label trial of the mRNA-1273 vaccine in adults aged 56 years and older showed a dose- and time-dependent robust immune response among these older adults.
Measured binding and neutralizing antibodies were not dependent on age and were commensurate with levels earlier reported among adults aged 18 to 55 years.
In phase 3 randomized, observer-blinded, placebo-controlled trial conducted at 99 centers across the United States, adults aged 65 years or older had a reported VE of 86.4% (61.4–95.2) against an overall VE of 94.1% (89.3–96.8).
Although the Pfizer and Moderna trials were not designed to measure the impact on transmission explicitly, real-world studies have shown associated vaccine benefits in reducing incidences of SARS-CoV-2 infections. In a metadata study of 280 nursing homes (NH) across 21 states in the United States, Mor and colleagues
used resident-level data to compare the rate of new resident infections as well as hospital transfers and/or deaths in facilities with early versus later vaccination clinics, adjusting for infection rates in each facility. Among early recipients of 2 doses of the mRNA vaccines, the investigators reported a magnitude of 5.2 fewer cases per 100 at-risk NH residents and an average cumulative reduction in hospitalization or death of 5 events per 100 infected residents per day up to 7 weeks.
reported significantly lower rates of SARS-CoV-2 infection and hospitalization for severe COVID-19. Following up with residents up to 6 weeks after receiving a third dose of the BNT162b2 mRNA vaccine, the investigators observed an incidence ratio of 0.29 for overall infection and 0.20 for hospitalization, which corresponded to a relative rate reduction of 71% and 80%, respectively.
Effectiveness of a Second COVID-19 Vaccine Booster Dose Against Infection, Hospitalization, or Death Among Nursing Home Residents — 19 States, March 29–July 25, 2022.
studied the additional role a fourth vaccine dose plays in reducing morbidity and mortality from COVID-19. Comparing a single mRNA COVID-19 vaccine booster dose, with a second booster dose, they found that a second booster dose provided additional protection against COVID-19-associated severe outcomes among NH residents during the Omicron period. Other smaller studies have reported similar protection among NH residents who have received the fourth vaccine dose to date.
Effectiveness of a fourth dose of covid-19 mRNA vaccine against the omicron variant among long term care residents in Ontario, Canada: test negative design study.
It is not clear what exact role and magnitude T cells play in protection from SARS-CoV-2, but they play a role in other viral infections in disease mitigation once infected. Owing to the prevailing realities of immunosenescence and inflammaging, older adults tend to have impaired vaccine-specific T-cell responses. Following 2 doses of the BNT162b2 mRNA vaccine, the frequencies of vaccine-specific IFNγ+ and IFNγ+IL-2+TNFα+ CD4+ and the frequency of specific CD8+ T cells were lower in COVID-19-naive older adults than in COVID-19-naive young adults.
T-cell responses were the same in the older and younger populations that were vaccinated after prior COVID-19. Several studies specifically address issues related to immunosenescence and inflammaging. Palacios-Pedrero et al observed lower vaccine-specific responses in the older group, and interestingly found a correlation between naive CD4+ cells and reduced vaccine-induced CD4 cells. This finding supports a major component of immunosenescence: poorer response in the aged is due to loss of naive cells.
demonstrated that older persons display less frequency and polyfunctionality of vaccine-induced T cells. Potentially demonstrating elements of both immunosenescence and inflammaging, they found that aging-related lower thymic function, altered T-cell homeostasis, proinflammatory monocyte profile, and altered dendritic cell features and function were associated with these reduced responses.
Effectiveness and Immunogenicity of the Non-mRNA Vaccines in Older Adults
The Novavax NVX-CoV2373 is a recombinant nanoparticle vaccine against SARS-CoV-2 that contains the full-length spike glycoprotein (S-protein) of the prototype strain plus Matrix-M adjuvant that is administered in 2-dose primary series 21 days apart. In a phase 3 randomized placebo-controlled trial conducted in the United Kingdom that included 1953 older adults aged between 65 and 84 years, the NVX-CoV2373 recorded a VE of 88.9% (20.2–99.7) followed up for a median of 56 days after the second dose. This VE compares impressively with the 89.8% VE reported for participants younger than 65 years.
A similar phase 3 trial conducted in the United States and Mexico for a median follow-up of 64 days after the second dose reported a VE of 91% in participants at overall high risk for COVID-19, defined as subjects aged 65 years or older and those of any age with chronic health conditions or an increased risk for COVID-19 due to elevated exposure.
Among older adults, in a phase 2 immunogenicity trial, a homologous booster dose of the NVX-CoV2373 vaccine administered approximately 6 months following the primary 2-dose series resulted in a significantly enhanced immunogenicity producing S-protein IgG and neutralization titers that were 4-fold higher than after the primary 2-dose series. Subgroup analysis for the ancestral Wuhan-Hu-1 strain showed slightly lower antibody responses in older adults (aged 60–84 years) than those in younger adults (aged 18–59 years).
Safety and immunogenicity following a homologous booster dose of a SARS-CoV-2 recombinant spike protein vaccine (NVX-CoV2373): a secondary analysis of a randomised, placebo-controlled, phase 2 trial.
The Jansen’s Ad26.COV2.S vaccine is a recombinant, replication-incompetent human adenovirus type 26 vector encoding full-length SARS-CoV-2 S-protein in a prefusion-stabilized conformation administered as a single-dose primary vaccination. In the initial phase 3 trial, participants aged 60 years or older had a VE of 76.3% (61.6–86.0) against moderate to severe-critical COVID-19 and a VE of 74.5% (57.9–84.3) against severity-adjusted symptomatic COVID-19, both higher than the overall VE reported in all age groups.
Remarkably, although estimates of VE differed between older adults with or without coexisting conditions at short-term follow-up, they became similar with a longer follow-up time. The final analysis of the trial reported a VE of 55.0% (42.9–64.7) after 14 days of follow-up, which dropped to 46.6% (30.7–59.0) beyond 28 days among participants older than 60 years.
This drop in efficacy between the primary and final analysis is believed to be due to more virulent circulating variants of SARS-CoV-2 that emerged after the primary analysis was carried out. In a double-blinded phase 3 randomized trial in which a homologous Ad26.COV2.S booster was administered 2 months after the primary series, efficacy against moderate to severe-critical COVID-19 among participants older than 60 years was 66.2% (−14.0–92.2) lower than the overall efficacy of 75.2% (54.6–87.3).
Efficacy, safety, and immunogenicity of a booster regimen of Ad26.COV2.S vaccine against COVID-19 (ENSEMBLE2): results of a randomised, double-blind, placebo-controlled, phase 3 trial.
However, the development of vaccine-induced thrombotic thrombocytopenia has limited the continued use of the Ad26.COV2.S vaccine either as a primary series or a booster
and thus limited its further use among older adults; many of whom have comorbid conditions that predispose them to thrombotic events.
The ChAdOx1 nCoV-19 (AZD1222) is a replication-defective adenovirus-vectored vaccine expressing the full-length SARS-CoV-2 spike glycoprotein gene. The vaccine is administered in a prime-boost regimen 4 weeks apart and has been shown to have similar immunogenicity across age groups.
Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial.
After 15 days or more follow-up in a double-blind, randomized placebo-controlled phase 3 trial, older adults had an estimated VE of 83.5% (54.2–94.1) that was better than the overall 74.0% (65.3–80.5) observed for all age groups.
A homologous booster dose of ChAdOx1 nCoV-19 given 6 to 8 months after completion of the primary series produced similar levels of boosting effect on anti-spike IgG and cellular responses after 28 days between older adults aged 70 years or older and adults aged between 18 and 69 years.
Safety and immunogenicity of seven COVID-19 vaccines as a third dose (booster) following two doses of ChAdOx1 nCov-19 or BNT162b2 in the UK (COV-BOOST): a blinded, multicentre, randomised, controlled, phase 2 trial.
The Gam-COVID-Vac (Sputnik V) is a recombinant adenovirus (rAd)-based vaccine that contains the full-length SARS-CoV-2 glycoprotein S gene. The vaccine is administered in a prime(rAd26)-boost(rAd5) regimen, 21 days apart. Despite the halt in its emergency use and approval by the WHO,
the Sputnik V vaccine showed good efficacy among older adults. Although the initial safety and immunogenicity trial did not include adults older than 60 years,
Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia.
the phase 3 trials conducted in Russia had 2144 adults older than 60 years completing the study. At a median follow-up time of 48 days after the first dose, VE among this older age group was reported to be 91.8% (67.1–98.3), slightly higher than the overall efficacy of 91.6% (85.6–95.2).
Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia.
The CoronaVac (Sinovac Life Sciences) is an inactivated whole virus vaccine that has been shown to have immunogenicity and efficacy against COVID-19. CoronaVac, when administered in the standard 2-dose regimen 28 days apart, produces immunogenicity in adults aged 60 years and older, which is similar to adults aged 18 to 59 years, in a dose-dependent manner.
Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine (CoronaVac) in healthy adults aged 60 years and older: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial.
Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18–59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial.
A phase 3 trial of adults aged 70 years and older in Brazil found adjusted VE against hospital admissions was 55.5% (46.5% to 62.9%) and against deaths was 61.2% (48.9% to 70.5%) at greater than equal to 14 days after the second dose.
Effectiveness of the CoronaVac vaccine in older adults during a gamma variant associated epidemic of covid-19 in Brazil: test negative case-control study.
A decline in effectiveness particularly in those older than 80 years was also reported. CoronaVac-induced antibodies tend to wane at a faster rate in older adults after the primary series but tend to be more durable after the third dose. For instance, older adults (aged 60 years or older) in a single-center phase 2 trial had an approximate decline of 10.7-fold in neutralizing antibodies 6 months after the second dose of the CoronaVac vaccine versus 6.8-fold observed for adults between 18 and 59 years. However, the rate of decline after a third dose given 8 months after the second dose was 2.5-fold among older adults versus 4.1-fold in the 18 to 59-year-old cohort over the same period.
Although Covaxin (BBV152, Bharat Biotech International) does not seem to be currently in production or distribution, it was overwhelmingly the predominant vaccine initially used in India. The BBV152 is a whole-virion inactivated SARS-CoV-2 vaccine formulated with a Toll-like receptor 7/8 agonist molecule adsorbed to alum (Algel-IMDG) administered in a 2-dose regimen 4 weeks apart.
A total of 1858 older participants aged 60 years or older participated in the phase 3 trial and were found to have a modestly reduced VE to symptomatic disease of 67.8% (8.0–90.0) after a median follow-up of 99 days compared with 79.4% (66.0–88.2) VE in those younger than age 60 years.
Efficacy, safety, and lot-to-lot immunogenicity of an inactivated SARS-CoV-2 vaccine (BBV152): interim results of a randomised, double-blind, controlled, phase 3 trial.
Protection against omicron (B.1.1.529) BA.2 reinfection conferred by primary omicron BA.1 or pre-omicron SARS-CoV-2 infection among health-care workers with and without mRNA vaccination: a test-negative case-control study.
Vaccination following a previous SARS-CoV-2 infection increases all SARS-CoV-2-specific immunologic parameters due to the activation of immunologic memory generated from prior exposure.
This prior antigenic exposure has direct beneficial quantitative and qualitative effects on vaccine response in older adults. Vaccine-induced neutralizing and non-neutralizing antibodies are markedly increased among NH residents who had recovered from prior infection to the levels comparable to the younger comparator group
found that a longer interval between previous SARS-CoV-2 infection and vaccination results in a higher antibody response 2 and 6 months postvaccination among NH residents. This finding is consistent with studies that observed an enhanced humoral response using a 2-dose SARS-CoV-2 regimen with extended intervals.
it is thus interesting to note that an appropriate dosing interval, especially in convalescent elderly vaccinees, may overcome this initial diminished immune response to produce a robust response.
However, there has been a dramatic turnaround in this trend with the older adult population accounting for the largest percentage of vaccinated individuals in the United States at the time of writing this review.
Factors such as lower life expectancy, concerns about side effects, and efficacy historically influence vaccine uptake in this population. For COVID-19 vaccines, safety was the primary concern reported among unwilling older adults followed by doubts about their effectiveness and misinformation.
Factors Associated With Willingness to Receive a COVID-19 Vaccine Among 23,819 Adults Aged 50 Years or Older: An Analysis of the Canadian Longitudinal Study on Aging.
Notable misinformation included the belief of long-lasting immunity once infected with SARS-CoV-2, protection by certain blood group types, and erroneous belief of magnets or chips implanted in vaccines among others.
reported a significant unwillingness to receive the COVID-19 vaccines among female subjects and African American subjects. These subjects were, however, willing to discuss this uncertainty/unwillingness with their healthcare providers, suggesting an essential rolehealthcare providers may play in the battle against vaccine hesitancy.
Generalist and Subspecialist Physicians’ Knowledge, Attitudes, and Practices Regarding Influenza and Pneumococcal Vaccinations for Elderly and Other High-Risk Patients: A Nationwide Survey.
In a community-based multidisciplinary study of more than 20,000 adults older than 60 years in Singapore, direct contact and clarity in communication using mutually understood languages as well as direct access and consultation with allergists were found to significantly increase the willingness of unvaccinated enrollees to receive the COVID-19 vaccine after a 3-month follow-up.
Generalist and Subspecialist Physicians’ Knowledge, Attitudes, and Practices Regarding Influenza and Pneumococcal Vaccinations for Elderly and Other High-Risk Patients: A Nationwide Survey.
Furthermore, influenza vaccination or a willingness to receive the vaccine was strongly associated with a willingness to receive COVID-19 vaccines among older adults.
Factors Associated With Willingness to Receive a COVID-19 Vaccine Among 23,819 Adults Aged 50 Years or Older: An Analysis of the Canadian Longitudinal Study on Aging.
Thus, approaches that have been used in improving the uptake of influenza vaccines may be beneficial in increasing COVID-19 vaccine coverage among older adults.
Considering that reactions result from immune system activation, it is not so surprising that older adults do not have as many side effects from vaccines because they generate less robust responses.
In addition, reactions such as injection site pain, headache, and muscle pain may be more tolerable by older adults and as such, may be underreported among this age group.
Accordingly, the COVID-19 vaccines currently in use have all demonstrated good safety profiles among older adults with reactogenicity mostly mild to moderate.
Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial.
For instance, there are fewer local and systemic reactions reported among older adults (aged ≥65 years) following the 2-dose mRNA-based COVID-19 vaccines compared with younger adults (aged <65 years).
Safety of an inactivated, whole-virion COVID-19 vaccine (CoronaVac) in people aged 60 years or older in Hong Kong: a modified self-controlled case series.
A third dose of the BNT162b2 mRNA vaccine had mild to moderate side effects among participants aged 65 to 85 years in the Pfizer trials, like that of the second dose with no unsolicited adverse event.
The Novavax trials reported a lower incidence of local and systemic reactions among participants older than 65 years compared with younger participants.
Owing to the negative relationship between age, reactogenicity, and immunogenicity, it has often been hypothesized that reactogenicity could be related to immunogenicity. Certain groups found somewhat modest relationships between these 2 immunologic phenomena concerning the COVID-19 vaccines,
Differences in the study setting, analytical model, and manner of soliciting for vaccine reactions may have contributed to the differences in these findings. Nevertheless, older adults are known to report fewer postvaccination side effects and achieve lower antibody production compared with younger adults. This association needs further exploration through larger studies.
Proposed strategies to optimize vaccines for older adults
With the attendant reality of immunosenescence and inflammaging, a focused vaccine strategy that considers these immunologic effects could be helpful for older adults. A challenging feature of SARS-CoV-2 is its mutation ability leading to the production of more infectious and immune-escaping variants of concern. Although monovalent vaccines have some cross-variant activity,
the bivalent vaccines recently approved for use have shown better neutralizing capacities and could provide better protection against the immune-evasive Omicron family.
The initial bivalent vaccine approved by the European Union authorities adds the early Omicron BA1 strain to the Wuhan-containing current vaccine, and the version approved in the United States adds the more recent Omicron BA4/5. Chalkias and colleagues
studied the immunogenicity of the bivalent BA1 vaccine in a population that had 40% of subjects aged 65 years or older. The investigators found superior anti-omicron neutralization compared with the monovalent vaccine.
These data would suggest that the bivalent vaccine might be effective, but the clinical efficacy data of the bivalent vaccine are not yet available.
Overall, it is imperative that older adults are up to date with vaccinations because progressively significant benefits have been established with each extra dose administered in this age group.
In a study of NH residents and healthcare workers, the authors observed that a booster dose is needed to achieve significant Omicron neutralization activity among this population even if they had an infection before the Omicron era.
In the current Omicron era, this is essential to protect this age group from the possible devastating effects of infection with the immune-escaping Omicron variants. This additional dose was also shown to reduce transmission among NH residents compared with the primary vaccine series alone.
Effectiveness of a COVID-19 Additional Primary or Booster Vaccine Dose in Preventing SARS-CoV-2 Infection Among Nursing Home Residents During Widespread Circulation of the Omicron Variant — United States, February 14–March 27, 2022.
Severe Acute Respiratory Syndrome Coronavirus 2 Adaptive Immunity in Nursing Home Residents Following a Third Dose of the Comirnaty Coronavirus Disease 2019 Vaccine.
Dynamics of the Cellular and Humoral Immune Response After BNT162b2 Messenger Ribonucleic Acid Coronavirus Disease 2019 (COVID-19) Vaccination in COVID-19-Naive Nursing Home Residents.
Like the timing of vaccination after infection with SARS-CoV-2 as discussed earlier, modifications in the intervals between doses may help boost vaccine-induced immunity. Older adults 80 years or older receiving the 2-dose BNT162b2 mRNA vaccine at an extended interval of 11 to 12 weeks were found to produce a peak antibody response 3.5 times those that received the standard regimen 3 weeks apart. However, peak cellular responses were lower
In like manner, an extended-interval protocol for the adenovirus-based ChAdOx1 vaccine has increased spike-specific antibody responses by 2.3-fold and improved VE across all age groups.
Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials.
Although this carries the risk of extending the period of partial vaccination, a single dose of the BNT162b2 vaccine produces favorable immunogenicity and clinical efficacy
Effectiveness of the Pfizer-BioNTech and Oxford-AstraZeneca vaccines on covid-19 related symptoms, hospital admissions, and mortality in older adults in England: test negative case-control study.
Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials.
COVID-19 vaccine coverage in health-care workers in England and effectiveness of BNT162b2 mRNA vaccine against infection (SIREN): a prospective, multicentre, cohort study.
Thus, the timing of subsequent doses could be targeted appropriately using the half-life of vaccine-induced antibodies.
An initial 3-dose series could be considered in this setting where the vaccine is a neoantigen vaccine because it is not boosting prior immunity but rather must generate a response from naive cells. A 3-dose series could allow several benefits as observed by our data and those of others. One benefit is the increased breadth of response that particularly occurs with the third dose providing better anti-Omicron immunity. The other benefit is that the third dose boosted antibody levels among the hyporesponders to the primary series; this is a subset of the older multimorbid NH resident population that produced negligible or very low vaccine-induced antibodies similar to the levels observed in immunocompromised individuals. Previously, immunocompromised adults received a Centers for Disease Control and Prevention recommendation for a 3-dose series.
Thus, adopting a 3-dose vaccination schedule may be beneficial for this population of hyporesponders, and by extension, older adults; this would particularly apply to neoantigen vaccines. Alternatively, screening this population for possible hyporesponsiveness can help identify those who would need extra doses and thus, optimize protection for these adults.
Dynamics of the Cellular and Humoral Immune Response After BNT162b2 Messenger Ribonucleic Acid Coronavirus Disease 2019 (COVID-19) Vaccination in COVID-19-Naive Nursing Home Residents.
Moreover, heterologous boosting, which involves the administration of booster doses from a platform other than that of the primary series, has shown some effectiveness in enhancing protection against COVID-19. This strategy helps to maximize the quantity and breadth of vaccine-induced antibodies.
This carries the potential for antibody diversity owing to the subtle differences that have been described between the 2 mRNA vaccines currently in use
Heterologous versus homologous COVID-19 booster vaccination in previous recipients of two doses of CoronaVac COVID-19 vaccine in Brazil (RHH-001): a phase 4, non-inferiority, single blind, randomised study.
In a large cohort study among veterans, the incidence of infection and moderate-to-severe disease was significantly reduced among those who had been primed with an adenoviral vaccine and were boosted with an mRNA vaccine compared with those who had homologous vaccination with either the adenoviral or mRNA vaccines.
More investigation is clearly needed in the older population to determine the optimal primary series, booster schedules, and booster vaccine products that could apply to both COVID-19 and new pathogen outbreaks.
Summary
Vaccination remains a key tool in protecting older adults against severe outcomes of COVID-19. Thus, this population should remain of high priority for vaccination campaigns and must be kept up to date on additional doses for optimal protection. Vaccine protocols and formulations could be adapted to cater to the attendant immune changes in this population. Considering the high likelihood of hyporesponders to vaccination in this group, appropriate screening measures should be put in place. Finally, vaccination protocols should be tailored to maximize the benefits in this population and, with the robust benefits of a third dose among older adults, a 3-dose regimen with modified intervals should be considered, as well as heterologous boosting.
Clinics care points
•
Due to the high risk of SARS-CoV-2 infection in the older population, they should remain a high priority for vaccination campaigns and must be kept up to date on additional doses for optimal protection.
•
A 3-dose primary series enhances antibody production and breadth significantly providing better cross-variant protection and could be considered.
•
Older adults who report no vaccine side effects and/or have never been infected with SARS-CoV-2 should be prioritized when screening for vaccine responsiveness.
Acknowledgement
This work was supported by NIH AI129709-03S1, U01 CA260539-01, and CDC 200-2016-91773.
References
COVID-19 nursing home data - centers for Medicare & Medicaid Services data.
Coronavirus Disease 2019 (COVID-19) Outbreak Associated With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) P.1 Lineage in a Long-Term Care Home After Implementation of a Vaccination Program—Ontario, Canada, April–May 2021.
Effectiveness of the Pfizer-BioNTech and Oxford-AstraZeneca vaccines on covid-19 related symptoms, hospital admissions, and mortality in older adults in England: test negative case-control study.
Characteristics associated with serological COVID-19 vaccine response and durability in an older population with significant comorbidity: the Danish Nationwide ENFORCE Study.
Significant Reduction in Vaccine-Induced Antibody Levels and Neutralization Activity Among Healthcare Workers and Nursing Home Residents 6 Months Following Coronavirus Disease 2019 BNT162b2 mRNA Vaccination.
Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia.
Impact of age, ethnicity, sex and prior infection status on immunogenicity following a single dose of the BNT162b2 MRNA COVID-19 vaccine: Real-world evidence from healthcare workers, Israel, December 2020 to January 2021.
Effectiveness of a Second COVID-19 Vaccine Booster Dose Against Infection, Hospitalization, or Death Among Nursing Home Residents — 19 States, March 29–July 25, 2022.
Effectiveness of a fourth dose of covid-19 mRNA vaccine against the omicron variant among long term care residents in Ontario, Canada: test negative design study.
Safety and immunogenicity following a homologous booster dose of a SARS-CoV-2 recombinant spike protein vaccine (NVX-CoV2373): a secondary analysis of a randomised, placebo-controlled, phase 2 trial.
Efficacy, safety, and immunogenicity of a booster regimen of Ad26.COV2.S vaccine against COVID-19 (ENSEMBLE2): results of a randomised, double-blind, placebo-controlled, phase 3 trial.
Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial.
Safety and immunogenicity of seven COVID-19 vaccines as a third dose (booster) following two doses of ChAdOx1 nCov-19 or BNT162b2 in the UK (COV-BOOST): a blinded, multicentre, randomised, controlled, phase 2 trial.
Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia.
Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine (CoronaVac) in healthy adults aged 60 years and older: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial.
Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18–59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial.
Effectiveness of the CoronaVac vaccine in older adults during a gamma variant associated epidemic of covid-19 in Brazil: test negative case-control study.
Efficacy, safety, and lot-to-lot immunogenicity of an inactivated SARS-CoV-2 vaccine (BBV152): interim results of a randomised, double-blind, controlled, phase 3 trial.
Protection against omicron (B.1.1.529) BA.2 reinfection conferred by primary omicron BA.1 or pre-omicron SARS-CoV-2 infection among health-care workers with and without mRNA vaccination: a test-negative case-control study.
Factors Associated With Willingness to Receive a COVID-19 Vaccine Among 23,819 Adults Aged 50 Years or Older: An Analysis of the Canadian Longitudinal Study on Aging.
Generalist and Subspecialist Physicians’ Knowledge, Attitudes, and Practices Regarding Influenza and Pneumococcal Vaccinations for Elderly and Other High-Risk Patients: A Nationwide Survey.
Safety of an inactivated, whole-virion COVID-19 vaccine (CoronaVac) in people aged 60 years or older in Hong Kong: a modified self-controlled case series.
Effectiveness of a COVID-19 Additional Primary or Booster Vaccine Dose in Preventing SARS-CoV-2 Infection Among Nursing Home Residents During Widespread Circulation of the Omicron Variant — United States, February 14–March 27, 2022.
Severe Acute Respiratory Syndrome Coronavirus 2 Adaptive Immunity in Nursing Home Residents Following a Third Dose of the Comirnaty Coronavirus Disease 2019 Vaccine.
Dynamics of the Cellular and Humoral Immune Response After BNT162b2 Messenger Ribonucleic Acid Coronavirus Disease 2019 (COVID-19) Vaccination in COVID-19-Naive Nursing Home Residents.
Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials.
COVID-19 vaccine coverage in health-care workers in England and effectiveness of BNT162b2 mRNA vaccine against infection (SIREN): a prospective, multicentre, cohort study.
Heterologous versus homologous COVID-19 booster vaccination in previous recipients of two doses of CoronaVac COVID-19 vaccine in Brazil (RHH-001): a phase 4, non-inferiority, single blind, randomised study.
00094-0&id=gr1.jpg){kind=link}