COVID-19 in the elderly people and advances in vaccination approaches

ABSTRACT

The rapid worldwide spread of the COVID-19 pandemic, caused by the newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in tens of millions of infections and over one million deaths. SARS-CoV-2 infection affects all age groups; however, those over 60 years old are affected more severely. Moreover, pre-existing co-morbidities result in higher COVID-19-associated mortality in the geriatric population. This article highlights the associated risk factors of SARS-CoV-2 infection in older people and progress in developing COVID-19 vaccines, especially for efficient vaccination of the older population. There is also a summary of immunomodulatory and immunotherapeutic approaches to ameliorate the outcome of COVID-19 in older individuals.

KEYWORDS:

• SARS-CoV-2
• covid-19
• elderly people
• vaccine

Coronavirus disease 2019 (COVID-19) is a newly emerged severe contagious disease, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).¹ The rapid worldwide spread of the virus has resulted in tens of millions of infections and over one million deaths. Although the respiratory system is primarily affected, leading to severe pneumonitis and even death,² involvement of the gastrointestinal system, heart, kidneys, and nervous system is also being reported.³ Individuals of all age groups, sexes, races, and physiological conditions are equally susceptible to the virus, and it is assumed that most of the world population will be exposed in the near future⁴ if a vaccine does not become available soon. Moreover, elderly and immunocompromised individuals with other comorbidities such as diabetes, hypertension, cancer, asthma, and cardiovascular abnormalities are more severely affected with a higher rate of case mortality.^5–8 Notably, higher prevalence of the disease is reported in individuals above 60 y of age.^5,9 Additionally, a retrospective study conducted on 85 fatal SARS-CoV-2 cases reported a median age of 65.8 y for diabetes, cardiopulmonary diseases, and hypertension comorbidities.¹⁰ Furthermore, a study including 1625 fatal cases of COVID-19 was reported, and of those, 139, 578, and 850 patients were 60–69, 70–79, and 80 y of age or above, respectively,¹¹ supporting the higher COVID-19-associated mortality in the geriatric population.

Older age (60 y or above) is identified as the major risk factor for COVID-19.^5,9 Accordingly, waning health and weakening physiological functioning of vital organs, including the respiratory system, lead to impaired mucociliary clearance of foreign particles or micro-organisms in aged individuals.^12,13 Likewise, both innate and adaptive immune systems are reportedly weakened, and the possibility of underlying chronic diseases upsurges as age advances, leading to the higher acquisition of infections.¹⁴ Acute respiratory distress syndrome (ARDS) is the main clinical outcome of COVID-19, which is attributed to acute lung injury due to pneumonitis, primarily leading to the death of older individuals. In addition, intravascular coagulation and pulmonary embolism are also the leading causes of COVID-19-associated mortality, irrespective of the occurrence of severe pneumonitis. It is evident that elderly patients develop coagulation abnormalities leading to disseminated intravascular coagulation during the late stage of COVID-19, prompting stroke, heart attack, pulmonary embolism, and gangrene formation in various parts of the body.^15–18 Intravascular coagulation is a life-threatening condition that is currently managed using anticoagulants such as low molecular heparin while monitoring the risk of bleeding.^19,20 Autopsy studies showed the presence of thrombus and congestion in the lungs and various other organs, indicating abnormal coagulation leading to death.^21,22 The addition of prophylactic anticoagulants increases the survival rate and recovery from the disease in elderly patients, and is one of the reasons for reduced mortality related to COVID-19 now in July 2020 compared to February 2020. Host proteases such as TMPRSS2 and TMPRSS4 are required for cleavage of the spike protein for the virus to enter the host cell successfully. In elderly patients, protease levels were elevated, therefore enhancing successful virus entry and establishment of the virus infection.^23–25 Furthermore, poor nutrition, dehydration, and dementia, along with many other clinical complications, are also risk factors, especially in bedridden and frail patients.²⁶ Reduced immunity and organ function and age-related pathophysiological susceptibility also add to the vulnerability, infectivity, and attack rate of SARS-CoV-2 in the elderly population.²⁷ Furthermore, the expression of angiotensin-converting enzyme-2 (ACE2) receptor decreases with age, resulting in restricted protective effects of ACE2.²⁷ Negligence in this age group in timely diagnosis, therapeutic management, and adequate preventive measures might further widen the sphere of risk.

Based on clinical presentation, COVID-19 is divided into asymptomatic, mild, severe, and critical forms, among which asymptomatic and mild forms are very prevalent.²⁸ Fever is reported as the most common symptom of SARS-CoV-2 infection; however, a case series of 56 patients revealed that only a small number of elderly patients (older than 60 y) manifested fever, suggesting that fever is not common in SARS-CoV-2 infection in geriatric patients.⁵ Moreover, other respiratory symptoms such as cough, dyspnea, sore throat, and rhinorrhea, along with anorexia, headache, myalgia, anosmia, ageusia, and diarrhea, were also evident in COVID-19.^8,29 Although comprehensive analysis of age-specific COVID-19 clinical symptoms is lacking, the possibility of atypical and nonspecific symptoms in geriatric patients is highly expected, similar to that in other diseases.³⁰ Furthermore, a higher frequency of the severe form of COVID-19 with increased mortality is expected, necessitating the intensive care unit (ICU) for affected elderly patients. The laboratory hematological finding, severe lymphocytopenia, also seems to be more pronounced in older COVID-19 patients.⁵ In addition, elevated levels of lactate dehydrogenase (a marker for tissue damage), D-dimer (a marker for blood clots), and C-reactive protein (a marker for excessive inflammation or myocardial damage), and decreased platelet count were also observed in elderly COVID-19 patients.^31,32

The unavailability of specific treatments and vaccines raises concerns about the protection of immunocompromised older adults. However, multiple efforts made worldwide and the rapid pace of vaccine development ensure the availability of an effective COVID-19 vaccine soon.³³ In this context, many vaccine platforms are being explored globally, including non-replicating vectors, DNA, RNA, subunit structures, inactivated virus-like particles, and live-attenuated vaccines.³⁴ Moreover, as of September 28, 2020, 40 vaccine candidates were under clinical evaluation and 151 under preclinical evaluation.³⁵ Among these vaccine candidates, ChAdOx1-S (Oxford/AstraZeneca), inactivated vaccines of Sinovac, Wuhan Institute of Biological Products/Sinopharm, Beijing Institute of Biological Products/Sinopharm, LNP encapsulated mRNA vaccine of Moderna/NIAID and BioNTech/Fosun Pharma/Pfizer, protein subunit vaccine of Novavax and non-replicating viral vector adenovirus type 5 vector of CanSino Biological Inc./Beijing Institute of Biotechnology (Adenovirus Type 5 Vector), Gamaleya Research Institute (Adeno-based (rAd26-S+ rAd5-S), Janssen Pharmaceutical Companies (Ad26COVS1), and adenovector vaccine of Johnson and Johnson have reached Phase 3 clinical evaluation, while the adjuvanted recombinant protein (RBD-Dimer), a subunit vaccine (Anhui Zhifei Longcom Biopharmaceutical/Institute of Microbiology, Chinese Academy of Sciences) and mRNA vaccine of Curevac, are at stage 2 of clinical evaluation.^35–37 All these vaccines were administered through the intramuscular route and evaluated for 14–21 d (inactivated vaccines) or 28 d (mRNA vaccines), whereas information about the non-replicating viral vector vaccines (ChAdOx1-S, adenovirus type 5 vector) is not available.³⁵ The evaluation of immune response against these vaccines must have special considerations for older age people who are at increased risk and suffer severely due to COVID-19.^38–40 Immunosenescence or altered immune response in older ages may affect vaccine performance.^39,41 It is believed that inactivated vaccines might be effective in generating sufficient immune responses, but the risks in older age groups need to be evaluated.^34,41 Similarly, to ensure adequacy of the immune response against subunit vaccines, which is generally low, additional boosters might be required.^34,41 Non-replicating viral vector-based vaccines, which are novel platforms and yet to be evaluated, may also require special considerations in geriatric patients.^34,41 Nevertheless, little knowledge has been harnessed on vaccinal immunity and responses thereto using SARS-CoV-2 in older adults. To gain further insights on vaccine-generated immune responses and before taking any policy decision on implementing vaccine use in the older population, experimentation results based on older laboratory animal studies on SARS-CoV-1 infection must be revisited.⁴² In Russia, a few vaccine candidates have been explored, including inactivated, recombinant proteins, subunit vaccines (S protein), mRNA-based, and vectored vaccines.⁴¹ Russia-based Gamaleya National Research Center for Epidemiology and Microbiology has also completed Phase 2 clinical evaluations in June 2020 and human trials of two forms of COVID-19 vaccines at Sechenov University and Burdenko Military Hospital.⁴³ Sputnik V became the first registered vaccine against COVID-19 and its public use has been started.^44,45 In India, a few vaccine trials are underway, and the first indigenous coronavirus vaccine, COVAXIN, which is an inactivated vaccine, is undergoing phase II human clinical trials across the country.⁴⁶ This vaccine was developed by Bharat Biotech in collaboration with the Indian Council of Medical Research-National Institute of Virology.⁴⁶ It has received the approval of the Drug Controller General of India for phase I and II human clinical trials⁴⁶ and has produced strong immunogenicity without side effects, thus its Phase III trial is likely to start in India.⁴⁵ In addition to the ongoing efforts in developing effective vaccines, there is also a need to evaluate other available immunotherapeutic approaches, including monoclonal antibodies with a high neutralizing index, which are devoid of any side effects associated with live or inactivated vaccines.⁴⁷

Each of the vaccine candidates under clinical evaluation has advantages and disadvantages. Moreover, although live-attenuated or inactivated vaccines are potent, reinfection can occur. Similarly, a subunit vaccine candidate may be safe, but its potency is always a matter of concern.³⁴ Hence, while considering a vaccine candidate for older people, safety issues must be adequately addressed. Moreover, the weaker immune system of older individuals might not recognize and attack the SARS-CoV-2, requiring regular boosters/doses that amplify the strength of the vaccine, which may have serious side-effects.^48,49 Hence, when a vaccine is developed, it must be evaluated for its safety and efficacy against SARS-CoV-2 by clinical trials that include older people.⁴⁹ In this context, clinical trials such as NCT04475302, NCT04470609, NCT04417335, NCT04441047, NCT04383574, which are specially dedicated for evaluation of safety and immunogenicity of SARS-CoV-2 vaccine in people 60 y or older are very encouraging and may prove crucial for the prevention of the disease and related mortalities in this age group.

Studies have highlighted the age-related decrease in vaccine efficacy, which is due to a decline in the adaptive and inherent immune response. As the aging population is increasing globally, especially in developed countries, vaccine efforts must take into consideration age-related issues to ensure effective control of infectious diseases, including COVID-19. These efforts are necessary to ensure a healthier life for the elderly as life expectancy is increasing.⁵⁰ An effective vaccine must stimulate a broad T and B cell response, potentially overcoming the reduced immune function in the older population.³⁹ All possible efforts are being made to develop a safe and effective vaccine against SARS-CoV-2, but the global panic created by the prevailing situation of increasing disease occurrence hastens the evaluation process many folds. In this context, the vaccines against SARS-CoV-2 entered clinical trials within a remarkable time of just 6 months as compared to the typical 3 to 9 y required for other vaccines.⁵¹ However, the speed should neither affect the quality of released vaccines nor encourage the utilization of improper entities, as a substandard commercialized vaccine may result in severe health hazards or vaccine failure.

Enhancing immunity especially in elderly can be beneficial in overcoming respiratory infections including COVID-19.^52,53 Immune-enhancing strategies in the elderly need to be well taken care of so as to boost immunity which could aid in ameliorating the severity of COVID-19 disease development as well as to avoid SARS-CoV-2 infection. These include dietary intake of balanced and nutritious foods, nutraceuticals, probiotics, medicinal herbs, traditional medicines, and Ayurvedic products along with supplementation of zinc and vitamins (A, C, D, E, B₆ and B12).^54–61 Physical exercises including adopting Yoga in routine life also aid to maintain and improve proper biological functions of the body and enhance the immunity.

Various other immune potentiating and immunotherapeutic approaches such as convalescent plasma therapy,^47,62–64 antibodies (neutralizing antibodies, monoclonal antibodies), intravenous immunoglobulins (IVIg);^47,65–67 T cells and Natural killer (NK) cells based immunotherapies,^68–71 Toll-like receptors (TLRs),^72,73 cytokine therapies,⁷⁴ and various immunomodulatory drugs,^75–77 have all revealed promising results to safeguard health of COVID-19 patients.

Monoclonal antibodies (MAbs) have been produced that act specifically against SARS-CoV-2.^47,67 MAbs such as B38, H4, 47D11 have been found effective in producing higher neutralizing antibody titers in elderly thus can effectively protect from COVID-19.⁷⁸ They bind to RBD of S protein in SARS-CoV-2 thus inhibit binding of RBD and ACE receptor.^79,80 In one study, itolizumab (humanized anti-CD6 MAb) has been shown to be well tolerated in elderly people, reducing IL-6 levels, and producing favorable clinical outcome in COVID-19 patients.⁸¹ It has shown prospects for minimizing cytokine storm in elderly during COVID-19, even in those with multiple comorbidity and critically and severely ill patients.⁸² Similarly, MAbs LY-CoV555 of Eli Lilly and REGN-COV-2 of Regeneron Pharmaceuticals are under trials for use in COVID-19 patients.⁸³In the present scenario, self-isolation and self-quarantine have been enforced by many countries to mitigate this pandemic. Moreover, regular use of personal protective equipment (PPE), adoption of physical distancing, respiration etiquette, and hand hygiene are highly recommended for older people.⁸⁴ Furthermore, regular disinfection of the surroundings of geriatric people with effective disinfectants must be ensured to prevent contamination of surfaces by SARS-CoV-2 to reduce the chances of infection.⁸⁴ Mental health issues in the elderly are exacerbated because of social isolation, loneliness, financial issues due to an increase in online scams, and dependency on caregivers during COVID-19.⁸⁵ It is essential to ensure the protection of the elderly not only from COVID-19 but other physical and mental health issues related to the pandemic. Governments must implement alert systems and provide information through telehealth helplines to the elderly.

In conclusion, older people are being disproportionately affected by COVID-19. The severity of the disease is greater, and the mortality among this age group is higher than in other age groups. The high mortality level is due to higher proportions of comorbidities such as diabetes, heart issues, and lung problems along with compromised immunity. Vaccine development efforts should include older people in clinical trials to ensure the efficacy and safety of the vaccine in this increasing segment of the population, and to evaluate associated risks in older age groups along with assessing requirement of booster doses for amplifying immunity. To win the fight against COVID-19, the world must ensure that the elderly are well protected and supported.

Author contributions

All the authors substantially contributed to the conception, compilation of data, checking, and approving the final version of the manuscript, and agree to be accountable for its contents.

Acknowledgments

All the authors acknowledge and thank their respective Institutes and Universities.

Disclosure statement

All authors declare that there exist no commercial or financial relationships that could, in any way, lead to a potential conflict of interest.

Additional information

Funding

This compilation is a review article written by its authors and required no substantial funding to be stated.