The COVID-19 Vaccine Gamble—By luck they worked in the oldest, frailest people

Less than three years have passed since the world prepared for a mass roll-out of newly approved COVID-19 vaccines.¹ From the outset, older people with frailty took centre stage. This group had borne the brunt of the pandemic, with most excess deaths occurring in the oldest age groups.² It was recognised early on that it was essential that vaccines worked well in this patient population.³ Vaccines developed by Pfizer-BioNTech and Moderna were quick to publish results from Phase III trials and became the first to be widely used in the USA and Western Europe.^4,5 On the back of these reports, residents in care homes and older people with co-morbidities were among the first to be vaccinated as healthcare systems scrambled to avoid collapse under the pandemic threat. However, much of the evidence base for safety and efficacy had come from younger people, or older people free from comorbidity and frailty.¹ Both these early vaccines used novel vaccine technology based on viral mRNA, that had never been tested on older people with frail and senescent immune systems.^6,7 Therefore, the mass vaccine rollout represented a huge gamble, with enormous resources invested in the hope that the efficacy reported in these early studies in more robust individuals would translate to the ‘real world’, where frailty, comorbidity and immunoscenescence could potentially have resulted in a costly failure the world could ill afford.

Immunosenescence is a broad term used to describe declining immunity with advancing age. It includes both quantitative and qualitative aspects of immune system responses that are likely to impact on the observed safety and efficacy profile of vaccines. This might have been especially relevant to mRNA vaccines because their method of action involves considerable processing by competent immune systems. With advancing age there is a reduction in naive T cells available to respond to the vaccine, particularly CD8 T cells. The diversity of T cell receptors decline with ageing in both CD8 and CD4 cells and T cell survival is reduced, resulting in a significant quantifiable reduction in immunity. However, it is important to note that qualitative changes are important too, including the favoured production of short-lived effector T cells over memory precursor cells, resulting in an impaired response of T follicular helper cells to vaccination. The remaining T cells also have lower plasticity and ability to respond to new infections.⁷ B cell numbers remain more consistent with age but, due to a reduced expression of select proteins in old age, fewer functional antibodies are produced.⁸ Theoretically therefore, vaccines are likely to be somewhat less effective in older people. Also, many vaccine studies relied solely on surrogate markers of efficacy such as antibody titres, antibody isotypes and measurements of neutralising antibodies to specific pathogens. At the start of the COVID-19 pandemic, it was not clear how well these would translate to meaningful outcomes such as reduction in infection rates, hospitalisation and death. This uncertainty was true for all cases of COVID-19, but particularly for frail older people. Furthermore, the relative importance of cellular aspects of the immune response in COVD-19 is unclear, especially in older people, so antibody levels may not be adequate surrogates for immunity.⁹ Finally, the effectiveness of any medical intervention must be offset against its safety profile. Here again, the impact of immunosenescence on vaccine safety was even more uncertain. Though the risk of serious adverse events mediated by over-activation of the immune system is theoretically lower, this may be offset by increased predisposition to adverse events overall, as this is the hallmark of frailty. So, with many more questions than answers, many countries gambled on the effectiveness and safety of new COVID-19 on their frail elderly population.

It was a gamble that thankfully paid off. Numerous studies have reported that COVID-19 vaccines work in elderly or frail individuals. A cohort of nursing home residents with high comorbidity and frailty were evaluated six months after receiving their second dose of the BNT162B2 mRNA vaccine.¹⁰ Almost all met the accepted antibody threshold for protection and only one positive COVID-19 case was recorded during this time. The safety profile of the vaccine was good with only minor adverse events reported, and no significant association between frailty and incidence of adverse events was found. Another study investigated eight COVID-19 vaccines in elderly patients aged 60 and over and in younger adults.¹¹ They found the elderly group had a lower occurrence of adverse events and there was no significant difference in immunogenicity between the two groups. The BNT162B2 mRNA vaccine has also been investigated in elderly residents (mean age 86 years) of a long-term care facility.¹² Anti-SARS-CoV-2 IgG antibodies were measured before and after the first dose of the vaccine and then again after the second dose. Interestingly, those who had previously had COVID-19 obtained an acceptable serological response following just one dose of the vaccine. Antibody levels were not significantly associated with frailty, suggesting the immune system's response to vaccination remains robust where other body systems fail. By contrast, when the Moderna mRNA-1273 vaccine was investigated in residents of a retirement facility (median age 90 years),¹³ those with increased frailty had reduced antibody levels and affinity following the second dose of the vaccine. However, this was overcome following a booster dose at 6 months.

In a recent study published in this journal,¹⁴ Meijide Míguez and colleagues add to the existing evidence base for safety and efficacy in even the most elderly and frail members of society. They studied the impact of a booster dose of Pfizer/BioNTech's BNT162b2 vaccine in residents and workers of three Spanish care homes. The mean age of the care home resident group was over 84 years old and vaccination resulted in antibody levels well above the threshold considered protective against COVID-19, with similarly high levels in both the resident and worker populations. In common with the other mentioned studies, they found the immune response was especially strong in those who had contracted COVID-19, suggesting protection is additive. They also tested cellular immunity and found evidence for a cellular response in both resident and worker populations. Although the study was underpowered to find differences in clinically meaningful outcomes, we now know that there is an excellent correlation between these measures and the surrogate markers used in this study.¹⁵ So, the good news is that the gamble has paid off and there is broad agreement in the scientific community that COVID-19 vaccines saved many millions of lives during the early years of the pandemic,¹⁶ including those of frail older people and care home residents. Even the emergence of virus variants of special interest has done little to dent the observed efficacy.¹⁷

One cause for lament was that the gamble was taken at all. It ought to have been possible to design studies at the outset of the pandemic that specifically recruited this group of people so vaccination programmes could have been rolled out with greater confidence.¹ The exclusion of older people from clinical trials, often for no good reason,¹⁸ is well documented. It is critically important that experts in the care of older people advocate for their inclusion in future. This could include becoming more involved in the running of clinical trials in the general population. This is not only morally correct but will minimise harm from evidence gaps in the effectiveness and safety of new medicinal products caused by an avoidable mismatch between clinical trial and real world populations.

Conflicts of interest

The authors have no conflicts of interest to declare.