Can Physical exercise be an effective adjuvant before the potential COVID-19 vaccine? Insights from serological responses and severity of re-infected cases

As more than 37 million conrmed cases and 1 million deaths worldwide from COVID-19, we ied to think about supporting immunity, So, there are more than 150 coronavirus vaccines and clinical trials are being developed. The success of those vaccines depends mainly on immunologic memory. People who are at high risk of re-infection with COVID-19 don’t show any evidence of having B-cell memory. 10-20% of infected patients don’t develop antibody response. randomized controlled trials and cross-sectional studies proved variant results about the effect of chronic exercise on vaccination function. is an important adjuvant strategy for prevention of re-infection and for development of better protective responses following vaccination.


Abstract
Background: As more than 37 million con rmed cases and 1 million deaths worldwide from COVID-19, we ied to think about supporting immunity, So, there are more than 150 coronavirus vaccines and clinical trials are being developed. The success of those vaccines depends mainly on immunologic memory. People who are at high risk of re-infection with COVID-19 don't show any evidence of having B-cell memory. 10-20% of infected patients don't develop antibody response. randomized controlled trials and cross-sectional studies proved variant results about the effect of chronic exercise on vaccination function.
The aim of this review is to suggest that exercise is an important adjuvant strategy for prevention of re-infection and for development of better protective responses following vaccination.

Methods:
Embase, Medline and the Cochrane Central Register were used to search for speci c keywords such as "COVID-19" OR "SARS-CoV-2" AND "Re-infection" for relevant publications up to 1 st of Nov. 2020. The systematic review was performed using PRISMA protocol.

Results:
According to inclusion criteria, 6 case reports from search and one case from a press conference were identi ed. The average age of re-infected patients was 36 years. The average intervening period between initial infection and reinfection was 105 days. 75% of cases who have been tested for antibodies after 1 st infection were negative, and turned seropositive after second infection. 57% of cases developing re-infection had worse clinical manifestation.

Conclusion:
Regular moderate intensity exercise not only can enhance the secondary antibody response of B cell memory but also decrease the severity of re-infection and the adverse reactogenicity of potential vaccines under development.

Background
The COVID-19 pandemic is a critical moment in the 21th century. Statistics recorded more than 1 million deaths and more than 54 million con rmed cases worldwide (1) Concerning this global health emergency that is threatening many lives, Vaccine developers started working out trying to bring a vaccine to the market in a record time to alleviate the global crisis. (2) Owing to the urgent need to the vaccine, some developers are running the trial phases simultaneously with the clinical process for SARS-CoV-2. Hopefully more than 150 coronavirus vaccines are under development across the world. Hard efforts are being exerted to make nding such a vaccine possible, including the U.S. (3) Although the current vaccines under development offer great hopes, there is a major concern about the success of these vaccines in providing the desired protective immunity against infection.
Liao and colleagues didn't only explain the uncontrollable activation of immune system and its damaging effect on the lung milieu in severe COVID-19 patients but they also pointed out that there's no evidence in the early recovery period of B cell memory in the patients with the worst and the most serious outcomes. Therefore, they are more prone to be reinfected with COVID-19 and less likely to develop humoral immunity via antibodies by any possibly made vaccine. (4) According to Wu and Long et al series, this nding goes in agreement with that 10-20% of infected patients fail to develop antibody responses. On account of the rapid decline of their immune responses 16 days after initial infection, these patients are left at risk of reinfection. That's why the most important factor in predicting the success of any upcoming vaccine is the power of the generated immunologic memory after being infected. (5,6) Studies show effect of exercise on the immune response after vaccination. Comparing both physically active candidates and those of sedentary life styles in a cross-sectional study, the antibody responses to vaccines are greater in older adults exercising regularly. Another study compares cardiovascular and exibility trainings for 10 months in previously non-active participants. According to Woods et al., it is shown that cardiovascular exercise done about an hour 3 times each week, leads to increase in neuroprotection evaluated at 6 months after in uenza vaccination.
Moreover, chronic exercise improves the immune responses to new antigens. (7) The aim of this article is to report all the re-infection cases, and their characteristics and to explain the pathophysiologic Observational epidemiological studies and case reports addressing the re-infection with COVID-19 have been considered eligible.

Results
Literature search has identi ed 6 cases reported of being re-infected with COVID-19. A seventh case was identi ed from Melbourne Australia from a press conference of Daniel Andrews, Victoria's premier. (8- 13) Results show that 75 % of cases who have been tested for antibodies after rst infection (n=4) were negative, and turned seropositive after second infection. (Table 1, Figure 1) Results also show that 57% of cases developing re-infection had worse clinical manifestations, and required hospitalization despite mild or asymptomatic rst infection (Table 1, Figure 2) The average intervening period between initial infection and re-infection was 105 days, and the average age of reinfected patients was 36 years.
Data from those reports were scarce, reporting no details about comorbidities or body mass index of re-infected cases

Discussion
An under trial COVID-19 vaccine, analyzed by Sahin and colleagues, showed evident development of neutralizing antibodies and CD-8 response. However, the mRNA vaccine-induced B-cell response reached its highest two weeks after immunization and then declined afterwards. (14) The effect of SARS-COV-2 vaccine on the body's immune response was analyzed subsequent to the administration of two doses; the viral-induced antibody concentration seemed to diminish typically around day 43. This nding was in concordance with the results that Wu and Long et al have illustrated in response to the infection, thus clearly providing evidence of the feeble B-cell response to infection as well as vaccination. (5,6) The memory B cells produced during the primary immune response are speci c to the antigen involved during the rst exposure; in a secondary response, the memory B cells speci c to the antigen or similar antigens will respond. When memory B cells reencounter their speci c antigen, they proliferate and differentiate into plasma cells, which then respond to and clear the antigen; such clearance is achieved by what is called the secondary antibody response. It is regarded that that secondary antibody response is the most crucial event that can prevent re-infection with a certain pathogen. (15) In this context, Kapasi and colleagues tested the secondary antibody response re ective of B cell memory in old vs. young mice in response to bouts of exercise. Secondary antibody response appeared to be exercise dependent, because old mice that received 1 bout of intense exercise demonstrated increased anti-antibody levels compared with old nonexercising mice. Moreover, the old mice that received the booster immunization after undergoing 1 bout of intense exercise, have attained levels of anti-HSA antibodies comparable to those seen in the young mice. In accordance with our ndings, Long and colleagues have tested the vaccine responses of two groups of old aged individuals. They have succeeded in showing that antibodies in response to pneumococcal vaccine improved signi cantly following regular moderate intensity exercise. (16) Such ndings signify that exercise has the ability to not only improve the outcome of infected cases but to prevent reinfection and can improve the response of vaccinated individuals. This should be taken into account during the ongoing trials for a potential COVID-19 vaccine.
Another important concern, during development of the vaccine is the severity of re-infection when compared to the initial infection. As shown in Table 1  In spite of reduced vaccine immunogenicity in old age due to insu cient B-cell memory, a number of studies, particularly those of Cowling and associates, illustrated that the local and, to a lesser extent, the systemic reactogenicity of vaccines increased in older adults. This nding could be attributed to the reduction of Soleus Muscle Protein SOCSP3 due to lack of exercise and sedentary lifestyle, noting that SOCSP3 acts to repurpose IL-6 from a pure pro-in ammatory to a rather regulatory cytokine role. (18) Thus, exercise not only can improve the immunogenicity of a potential vaccine but can also decrease the severity of reinfection and the adverse reactogenicity of potential vaccines under development.

Conclusion
In conclusion, we found that not only was exercise important for the overall outcome of an infected patient but also crucial to a healthy memory B cell response. This is especially important after more than half of the documented cases of re-infection were found to have worse clinical manifestations than in their rst infection. This raises the possibility that regular cardiovascular exercise might be pivotal for both a stronger immune response and the prevention of a reinfection all together. Exercise might be bene cial as well in preventing the reactogenicity of the potential vaccines under development.   Severity of re-infection in reported re-infected cases Figure 3 Summary of bene cial effects of regular physical exercise on immunogenicity and reactogenicity of a potential COVID-19 vaccine