Several vaccines candidates for Covid-19 are advancing through phase 3 clinical trials1,2. A variety of platforms are being used to produce them. They include genetically modified adenoviruses, recombinant proteins, self-amplifying mRNA, DNA plasmids and even a live, attenuated bovine tuberculosis bacillus. Headlines broadcast good news: the vaccines have stimulated the production of antibodies in the people who received them. In healthy people age 18-55, this probably means that they have or are developing immunity. However, the elderly and other vulnerable people don’t have a strong, young immune system. As we age, the production of naïve T cells is severely impaired due to a decreased output of lymphoid cells from the bone marrow and the involution of the thymus3. At the same time, there is a smaller repertoire of T cell receptors. This immunosenescence contributes to the increased incidence and severity of infectious diseases and a decreased efficacy of vaccines3. In addition, B lymphocytes that are produced in bone marrow undergo changes that aggravate the degradation in the immune system4. The amount of naïve B cells decreases, while effector B cells increase. This leads to a reduction in the diversity of antigen presenting cells, which activate an adequate immune response in younger people4.

As aged T cells die, the thymus replenishes the T cell pool with naïve T cells. However, the thymus undergoes age-associated involution. Thymic output of new T cells to the peripheral T cell pool is reduced by 99% in most 70 year olds compared to newborns5,6. The size of the thymus decreases from birth at a rate of about 3% per year until middle age, and 1% per year thereafter7. Decreased production of naïve T-cells could be a major reason why the severity of Covid-19 increases with aging. T cells from older people tend to produce several clones. This skews the repertoire of T-cells toward previously encountered antigens, such as other coronaviruses. An expansion of terminally differentiated memory T cells maintains the number of T cells. As a result, the composition of the peripheral T-cells is continuously altered. This decreases one’s ability to respond to infectious challenge by a new virus, like SARS-CoV-2. The rate of mortality from Covid-19 increases substantially in the eighth decade of life. Consistent with this observation, fewer new T-cells are made after age 70. Moreover, thymic involution is more rapid in men. Still, there could be ways to slow this down. Researchers were to regenerate and reactivate the thymus gland in healthy aging men. A combination of recombinant human growth hormone (rHGH), the dietary supplement dehydroepiandrosterone (DHEA) and the prescription drug metformin was apparently able to reverse aging and the development of senescence in the neuroendocrine immune systems in people who participated in the clinical trial2,7,9. Metformin by itself can also extend human lifespan10,11. It reduces the incidence of cancer and mortality, while helping people retain proper cognitive function. It also favorably influences metabolic and cellular processes that are closely linked to the development of age-related problems. More importantly, it increases the lifespan of not just people who have diabetes, but also in slowing down the aging process. So, there is a clinical trial being planned called Targeting Aging with Metformin, or TAME. It will look at the effects of metformin alone on longevity10,11.

Still, elderly people do retain some immune responses. This is important when considering whether to vaccinate us and how to treat us, should we develop the Covid-19 disease. Unlike the very young, we have been exposed to many versions of coronaviruses that can cause the common cold12. Lymphocytes from 20–50% of unexposed blood donors react to SARS-CoV-2 antigen peptides. In a recent study, reactivity was detected in 50% of donor blood samples obtained in the USA between 2015 and 2018, before SARS-CoV-2 appeared in the human population13. Often, older people retain a low level of antibodies against the spike protein and other viral antigens. For many of us, this means that our immune systems will recognize similar antigens on the SARS-CoV-2 virus. As a result, we will produce an adequate immune response and eliminate the virus from our bodies. However, others of us may produce a lower level of antibodies that not only do not provide protection, but actually enable the virus to enter critical cells in our body, replicate themselves, spread further and cause Covid-19. This antibody dependent enhancement (ADE) is when the severity of a disease increases when an antibody worsens a pathogen’s virulence by an antibody-dependent mechanism14. Viruses can use preexisting non-neutralizing antibodies from previous exposure to invade host cells15. This is most commonly observed during secondary dengue virus infection, causing severe hemorrhagic disease. That is, the antibody can bind to the virus and bring it to T-cell receptors on cells in the lungs and critical immune cells. After binding, the virus enters the host cells. Currently, we are not able to tell the difference between any severe viral infection and an immune-enhanced disease. Vaccine enhancement of Covid-19 could occur in some people. This is when disease severity is enhanced in an infected person who was previously vaccinated against the virus compared to unvaccinated controls. Unfortunately, scientists have not discovered quantifiable, objective clinical signs or biomarkers that can be used to easily identify vaccine enhancement or ADE. The only way to see if a vaccine is effective is to expose vaccinated people to the virus, which is unethical. So, some of the most important clinical trials are being done on volunteers who are health care workers who work with Covid-19 patients. We should look for increased frequency of severe cases and atypical manifestations of infection. So, it will be wise to carefully analyze data from clinical trials15.

It is plausible to think that ADE occurs with SARS-CoV-215. Elderly patients are more susceptible to infection. Coronaviruses are highly prevalent in the global population. They cause cold and flu-like symptoms. So, seroconversion into previous circulating coronaviruses is probably widespread in the elderly. Thus, we tend to have a larger repertoire of antibodies against Coronavirus epitopes, which recently has been shown to expand during SARS-CoV-2 infection. However, whether these antibodies are neutralizers or enhancers is not yet known. The SARS-CoV-2 virus continues to mutate, with most mutations being within the coding sequence of the spike protein, It has been suggested that these mutations may be responsible not only for the spillover from animals to humans, but also for inducing ADE. This could happen if changes in spike protein epitopes increase interactions with non-neutralizing antibodies15.

So, it was encouraging when a recent study found that a vaccine based on the receptor binding domain (RBD) of the SARS-CoV-2 virus caused a robust neutralizing antibody response in rodents16. Importantly, anti-sera from immunized rodents did not mediate ADE of viral entry under conditions in which the Zika virus caused ADE. However, animal trials can be misleading. Only clinical trials with human subjects will provide useful data on safety16.

While we wait for the results of clinical trials, we can look at the coronavirus that caused the first SARS epidemic, SARS-CoV. Like the virus that causes dengue fever and HIV, the SARS-CoV virus was able to bind antibodies to the spike protein and use them to infect several types of immune cells, especially monocytes17. So, there is ample precedence of ADE in other viral infections. This includes not just dengue fever and the first SARS-CoV virus, but also a similar coronavirus that causes Middle East respiratory syndrome (MERS), as well as the viruses that cause measles, and respiratory synctial virus (RSV)18.

After the FDA and other countries’ regulatory agencies review the results of current clinical trials for vaccine candidates, we will know more about the effects on healthy people age 18-55. If the reviews are favorable and vaccines are approved, who will receive the vaccine? To the best of my knowledge, everybody agrees that healthcare workers should be among the first to be immunized. Certainly, they are included in the clinical trials. Many of them will be exposed to the SARS-CoV-2 virus again. So, we will see if ADE occurs in many (or any) of them. However, there is no such agreement about who else should be prioritized. Some suggest that children should be vaccinated because they have the most social contacts and are most likely to spread the virus. Others suggest that the elderly should be vaccinated instead, since we are the most vulnerable to the severe effects of Covid-19, including death. However, it is well known that the vaccines tend to be less effective in the elderly. Moreover, since most elderly people already have antibodies to similar coronaviruses that cause the common cold, we might be more susceptible to ADE. This might lead some people to think that we should avoid vaccinating the elderly and start with children – even though nobody under the age of 18 is a subject in the current clinical trials. One of my fears is that a vaccine will be shown to be safe and effective for now, but not when future mutants of the SARS-CoV-2 virus emerge, they will produce new serotypes, like those that occur in dengue fever. If the same type of ADE occurs in such future serotypes of SARS-CoV-2, children who were never in any danger before being vaccinated could be in grave danger.

So, I’m advising my friends and family to wait before they even think about letting their children be vaccinated. Wait until we can see the long-term effects of the vaccine. I don’t think my life is worth risking the lives of my dear grandchildren – or anyone else’s. I can stay isolated and wear a mask when I have to go out. I don’t need to risk anyone’s child. I even think that a society should be judged, in part, by the way they treat their children and other vulnerable people, including the elderly.

So, it’s noteworthy that China announced that it will not be necessary to vaccinate their entire population19. They are going to prioritize front line workers and people who have to travel – especially to other countries where the Covid-19 pandemic is still active. Their children and elderly will remain safe. In the meantime, they will continue to show the rest of the world how true viral tracking and isolation can work. Their scientists will continue collaborating with scientists around the world – regardless of the hate and stupidity that some of our politicians try to spread. Still, only love and education can stop hate and ignorance. Science and honesty will be essential if we are going to do a good job of limiting morbidity and mortality. We may or may not be able to end this pandemic and return to what we call ‘normal’.

Notes

1 Smith, R.E. Russia starts vaccinating its military personnel. Developing vaccines and treatments for Covid-19. Progress report. Wall Street International, 24 Aug., 2020. 2020.
2 Le, T.T. et al. The Covid-19 vaccine development landscape. Nature Reviews Drug Discovery, Vol. 19, p. 305-306, 2020.
3 Pangrazzi, L. and Weinberger, B. T cells, aging and senescence. Experimental Gerontology, Volume 134, Article 110887, 2020.
4 Suárez, V.S et al. Aspectos actuales de la organogénesis. Función e involución del timo. Revista Cubana Hematología, Inmunología y Hemoterapia, Vol. 29, p. 349-358, 2013.
5 Aspinal, R. and Andrew, D. Thymic involution in aging. Journal of Clinical Immunology, Vol. 20, p. 250-256, 2000.
6 Kadambari, S. et al. Why the elderly appears to be more severely affected by Covid-19: The potential role of immunosenescence and CMV. Reviews Medical Virology, Vol. 30, Article e2144, 2020.
7 Schwartz, M.D. et al. Decreased naïve T-cell production leading to cytokine storm as cause of increased Covid-19 severity with comorbidities. Aging and Disease, Volume 11, 742-745, 2020.
8 Fahy, G.M. et al. Reversal of epigenetic aging and immunosenescent trends in humans. Aging Cell, Article e13028, published online, 2019.
9 Smith, R.E. Can Aging Be Reversed? Wall Street International, 24 Dec., 2019.
10 Smith, R.E. Metformin (Glucophage) May Extend Lifespan. Wall Street International, 24 August, 2018.
11 Kulkarni, A.S. et al. Benefits of metformin in attenuating hallmarks of aging. Cell Metabolism, Vol. 32, p. 15-30, 2020.
12 Sette, A. and Crotty, S. Pre-existing immunity to SARS-CoV-2: the knowns and unknowns. Nature Reviews Immunology, Vol. 20, p. 457-458, 2020.
13 Grifoni, A. et al. Targets of T cell responses to SARS-CoV-2 coronavirus in humans with Covid-19 disease and unexposed individuals. Cell Vol. 181, p. 1489–1501, 2020.
14 Arvin, A.M. et al. A perspective on potential antibody dependent enhancement of SARS-CoV-2. Nature, Vol. 584, p. 353-363, 2020.
15 Peron, J.P.S. and Nakaya, H. Susceptibility of the elderly to SARS-CoV-2 infection: ACE-2 overexpression, shedding, and antibody-dependent enhancement (ADE). Clinics, Vol. 75, Article e1912, 2020.
16 Quinlan, B.D. et al. The SARS-CoV-2 receptor-binding domain elicits a potent neutralizing response without antibody-dependent enhancement. bioRxiv preprint, 12 April, 2020.
17 Yip, M.S. et al. Antibody-dependent enhancement of SARS coronavirus infection and its role in the pathogenesis of SARS. Hong Kong Medical Journal, Vol. 22, p. 25-31, 2016.
18 Lee, W.S. et al. Antibody-dependent enhancement and SARS-CoV-2 vaccines and therapies. Nature Microbiology, Vol. 5, p. 1185-1191, 2020.
19 Yeung, J. China says no need to vaccinate entire population against Covid-19 at this stage, only frontline workers, CNN, 14 Sept., 2020.