COVID-19 has raised many questions for scientists. Why are young children less likely to suffer from a severe form of coronavirus? Why is the death rate much lower in some countries than in others? What is the reason that many people do not get infected even with prolonged close contact with an infected COVID-19? Why do almost half of the people who test positive for COVID-19 have no symptoms?

The researchers suggested that the reason is the protective properties of previous vaccines that are not related to COVID-19. In response to the vaccine, the body produces many different antibodies to protect against the virus, since each part of the viral particle stimulates the production of different antibodies. Antibody tests detect the presence of a narrow set of antibodies but do not measure the power of all the different antibodies associated with the virus. Antibodies that the body has developed after various past vaccinations can form cross-protective immunity against SARS-CoV-2.

Another explanation is that some vaccines stimulate innate immunity by reprogramming cells of the natural immune system. This phenomenon is called trained immunity.

Trained immunity: innate immunity has memory

The vertebrate immune system is traditionally divided into innate and adaptive. Reactions of the innate immune system are non-specific, that is, similar to any pathogens. Adaptive immune system responses are specific, directed against a particular pathogen.

Cells of the innate immune system recognize pathogens and tissue damage through pattern recognition receptors (PRR). When PRR is activated, non-specific processes are activated: phagocytosis (digestion of solid particles by cells), cell movement, destruction of pathogens or cells, and production of cytokines – signaling molecules involved in the immune response. These innate immune mechanisms are high-speed and effective in eliminating invading pathogens.

Adaptive immune responses develop more slowly, but they are specific. The adaptive immune response involves dendritic cells, T-lymphocytes, and B-lymphocytes. These lymphocyte-dependent adaptive immune responses lead to long-term immunological memory.

The dogma that only adaptive immunity can create immunological memory has recently been challenged by research showing that innate immune responses in plants and invertebrates (organisms lacking adaptive immune responses) can increase resistance to reinfection. Besides, some mammalian vaccination models have demonstrated that protection against reinfection occurs independently of T and B lymphocytes. These studies have led to the hypothesis that innate immunity may be affected by previous encounters with pathogens or their products, and this property has been called “trained immunity ” or “innate immune memory”.

Trained immunity is based on changes in transcription programs and cell physiology. These changes increase the response to secondary stimulation by pathogens, increase the production of inflammatory mediators, and increase the ability to eliminate the infection.

Unlike long-term immunological memory formed by adaptive immunity, trained immunity depends on the altered functional state of innate immune cells, which persists for weeks or months, rather than years after the initial stimulus is eliminated.

An example of trained immunity is the non-specific protective effect against infections other than target diseases, live vaccines against smallpox, measles, polio, and BCG.

Non-specific protective effect of BCG and coronavirus

BCG is a vaccine against tuberculosis. Trials of the BCG vaccine in adults and children have shown that this vaccine causes non-specific activation of innate immune cells. BCG vaccination resulted in protection against yellow fever and malaria, driven by increased Pro-inflammatory activity of innate immune cells-monocytes.

There is evidence that BCG vaccination can cause antitumor immune effects leading to the prevention or treatment of malignancies such as bladder cancer, melanoma, leukemia, and lymphoma. These antitumor effects of BCG seem to depend on its ability to induce trained immunity in monocytes and macrophages.

Prior BCG vaccination increases the antibody response to many other vaccines that are subsequently administered. Dutch scientists have demonstrated that BCG vaccination accelerates the production of antibodies during subsequent flu vaccination. Also, in addition to enhanced Pro-inflammatory responses after BCG vaccination, non-specific effects of influenza vaccination were observed with the presence of cytokine responses against unrelated pathogens.

Scientists have suggested that two mechanisms explain the beneficial non-specific effects of BCG vaccination: cross-reactivity of T-lymphocytes (the ability of a T-lymphocyte to protect against multiple pathogens) and innate trained immunity.

These facts have led to speculation that BCG vaccination may play a role in protecting against COVID-19.

Randomized controlled trials have shown that the immunomodulatory properties of the BCG vaccine can protect against respiratory infections. In Guinea-Bissau, a country with a high mortality rate, BCG vaccination reduced all-cause infant mortality by 38%, mainly due to fewer deaths from pneumonia and sepsis. In South Africa, the BCG vaccine reduced the number of respiratory tract infections in adolescents by 73%.

SARS-CoV-2 is a single-stranded virus with positive RNA. In controlled trials, the BCG vaccine has been shown to reduce the severity of infections caused by other viruses with this structure. For example, the BCG vaccine reduced yellow fever viremia by 71%, and in two studies in mice, it significantly reduced the severity of the encephalomyocarditis virus. Thus, the BCG vaccine can reduce viremia after exposure to SARS-COV-2, resulting in a less severe form of COVID-19 and faster recovery.

BCG vaccine is used to fight tuberculosis infection all over the world, except for the USA, Germany, Spain, Italy and other countries. The researchers noted that countries that do not have BCG vaccination have ten times more severe course of COVID-19 and higher mortality. However, such studies are subject to significant distortion due to many factors, including differences in national demographics and morbidity, COVID-19 testing rates, and the stage of the pandemic in each country.

In March 2020, randomized controlled trials began in the Netherlands and Australia to help assess whether the BCG vaccine reduces the incidence and severity of COVID-19 in healthcare workers: NCT04327206, NCT04328441.

Until these trials are completed, or other evidence is available that BCG is useful as a protection against coronavirus, who does not recommend BCG vaccination to prevent COVID-19. However, who continues to recommend BCG vaccination for newborns in countries or places with a high incidence of tuberculosis.

One of the reasons for this approach is that a BCG vaccine introduced several decades ago in childhood is unlikely to protect against COVID-19 since the beneficial non-specific effects of the BCG vaccine can be changed by subsequent administration of another vaccine.

Another reason is that if the BCG vaccine is ineffective against COVID-19, BCG vaccination can cause a false sense of security. In addition, careful monitoring of safety in randomized trials to prevent the possibility that the increased immunity with BCG exacerbates COVID-19 in a minority of patients with severe disease.

Mumps vaccine as protection against SARS-CoV-2

American scientists have suggested that the measles, mumps and rubella (MMR) vaccine may reduce the severity of COVID-19.

The researchers looked at the different ways that people produce MMR-related antibodies, as each of them affects titer values differently. First, people may have antibodies from Merck’s current MMR II vaccine, originally licensed in 1979, which includes the Edmonston measles strain, the Jeryl Lynn mumps strain (level B), and the Wistar RA 27/3 rubella strain. Second, people may have antibodies from early monovalent vaccines against measles, mumps, or rubella. Third, people may have antibodies from other combination vaccines, including Merck’s original MMR vaccine, which uses the less significant HPV-77 DE-5 rubella strain. Finally, older people, including virtually everyone born before 1957, are more likely to have MMR antibodies from natural infections. Importantly, if someone was infected with the measles virus at some point, that person could have had up to 73% of their previous antibody repertoire removed.

The researchers divided 80 study participants who had recently been exposed to COVID-19 into two groups: those who had MMR antibodies from the MMR II vaccine (50 people), and those who had MMR antibodies from other sources, including previously transmitted measles, mumps, and rubella (comparison group, 30 people). The study showed that the higher the mumps titers associated with the MMR II vaccine, the easier the course of COVID-19, regardless of age. This relationship was not observed in the comparison group. There was also no association between the measles and rubella titers and the severity of COVID-19 in both groups.

Dependence of COVID-19 severity on IgG titers of mumps in MMR II group:

  • From 134 to 300 AU/ml – persons with functional immunity or asymptomatic.
  • Below 134 AU/ml-patients with mild symptoms.
  • Below 75 AU/ml-patients with moderate symptoms.
  • Below 32 AU/ml are patients who are hospitalized and need oxygen.

In the MMR II group, 5 out of 50 individuals had mumps titers of 182 AU/ml or higher, and all 5 of these subjects aged 21 to 41 were functionally immune. Issues with functional immunity tested negative in nasopharyngeal tests for SARS-CoV-2 or antibody tests for SARS-CoV-2. Each of them had several days of extensive contact with a person with active symptoms positive for SARS-CoV-2, such as a housemate or spouse. These subjects did not apply social distancing or other precautions, such as wearing masks. Despite this, issues with functional immunity have never tested positive for COVID-19, despite the ease of transmission of SARS-CoV-2.

Another demonstration of possible cross-protection of the MMR vaccine is the fact that the prevalence of COVID-19 in young children is seven times lower than in adults. The bulk of positive cases increases slowly at the age of 5, increases most sharply at the age of 14, and then peaks at the age of 21 with a prevalence of 2.17%, seven times higher than for the youngest ages.

After two MMR II vaccinations 5 years apart, IgG titers for rubella remained seropositive in 93% of people, IgG titers for measles remained seropositive in 82% of people, and IgG titers for mumps remained seropositive in 40% of people. Thus, the mumps titer is the only MMR titer that decreases by 9.2% per year after vaccination.

Based on the average annual rate of decrease in mumps titers of 9.2% and the maximum seropositive value for mumps titers of 300 AU/ml, the scientists calculated that the average mumps titer would decrease to 142 AU/ml 9 years after MMR II vaccination and to 130 AU/ml 10 years later. Based on the fact that the average age for a second MMR II vaccination of children in the United States is 5 years, the average age at which a child’s titers will drop below 134 AU/ml will be 14 years.

It is possible that the original MMR vaccine and other combination and monovalent vaccines, as well as previous infections with measles, mumps and rubella, may provide some level of protection against COVID-19. However, these relationships cannot be detected by titer tests alone, since older people with naturally acquired antibodies against mumps, measles, and rubella usually have high titer values of the measured antibodies, which may not match the antibodies that protect against COVID-19. Such high titers are most often point to natural antibodies, not the antibodies from the vaccination. In the study, all titers were significantly and positively correlated with age in the comparison group, indicating that older people were more likely to have antibodies from natural infections rather than from vaccination.

Although most MMR vaccines worldwide use the same strains of measles and rubella as Merck’s MMR II, at least 10 different mumps strains have been used in recent decades. In addition to Jeryl Lynn, the most commonly used mumps strains outside the United States are RIT 4385, Urabe, and L-Zagreb. If it turns out that the Geryl Lynn mumps strain in the MMR II vaccine can provide long-term cross-protective immunity against COVID-19, this does not mean that all mumps strains will have a protective effect.

Another possible protective mechanism of the MMR II vaccine against COVID-19 is that weakened vaccines induce a non-specific trained innate immunity that can act against COVID-19.

Flu vaccine as protection against COVID-19

TLR7 is a receptor that recognizes single-stranded RNA viruses such as SARS-CoV-2. The flu vaccine is also recognized by TLR7, which activates this receptor and possibly creates cross-protection against the coronavirus.

The flu vaccine enhances the functions of NK cells in the innate immune system-natural killer cells that recognize and kill infected cells in the absence of antibodies.

Italian scientists found that regions with higher flu vaccination rates had fewer deaths from COVID-19. For the 2019-2020 flu season, a quadrivalent inactivated cell-based influenza vaccine (QIV) was available for the first time in Italy and the rest of Europe, in addition to the trivalent inactivated vaccine (TIV) and the TIV adjuvant. The vaccine could stimulate trained innate immune memory, so when faced with SARS-CoV-2, the local lung immune system was set up to respond quickly. It could reduce the incidence of SARS-Cov-2 or ease the course of COVID-19. However, this scenario is more likely with a weakened flu vaccine, which is more likely to lead to the formation of locally trained immunity than an inactivated vaccine. Another explanation may be that higher-income groups with better overall health are more likely to be vaccinated against the flu.

Influenza vaccination is encouraged to reduce hospitalizations and help in the differential diagnosis of viral-mediated respiratory distress syndrome in adults, so the benefits of influenza vaccination are already known in regions where SARS-CoV-2 infection is observed. Further research is needed to determine whether there is any link between higher flu vaccination rates and lower covid-19 mortality rates.

In an American preprint study, researchers analyzed immunization data from 137,037 people who had PCR tests for SARS-CoV-2. Scientists have found that vaccines against polio, Hemophilus influenza type B (HIB), measles-mumps-rubella (MMR), chickenpox, influenza and hepatitis A/B (HepA-HepB) and pneumococcal conjugate vaccine (PCV13) administered over the past 1, 2, and 5 years are associated with a reduced incidence of SARS-CoV-2 infection. The association persisted even after adjusting for the geographical incidence of SARS-CoV-2 and testing rates, demographics, comorbidities, and the number of other vaccinations.

A Dutch-German preprint shows that SARS-CoV-2 infection was less common among Dutch hospital employees who received flu vaccinations during the 2019-2020 winter season. Using an in vitro model of trained immunity, scientists have demonstrated that a quadrivalent inactivated flu vaccine used in the Netherlands during the 2019-2020 flu season can induce a conditioned immune response, including improved cytokine responses, after stimulating human immune cells with the SARS-CoV-2 virus.

Swiss and Brazilian scientists in a preprint study analyzed data from 92,664 clinically and molecularly confirmed COVID-19 cases in Brazil to understand the potential link between flu vaccination and Covid-19 outcomes. Patients who had recently received the flu vaccine were 8% less likely to need intensive care, 18% less likely to need invasive respiratory support, and 17% less likely to die.

The risk of flu for people with cardiovascular diseases

An analysis by the American Heart Association, an organization for the prevention and treatment of cardiovascular diseases (CVD), found that for people with CVD, the flu shot significantly reduces the risk of death or severe heart complications.

The meta-analysis included 16 randomized and observational studies and covered the experience of more than 237,000 people. The analysis showed that the flu-vaccinated people were 18% less likely to die from heart disease, and 28% less likely to die from any cause. They are also 13% less likely to experience serious heart problems than those who haven’t had a flu shot.

The centers for disease control and prevention recommends that everyone over the age of 6 months should be vaccinated against the flu. That is especially important for adults 65 and older, who account for the vast majority of flu-related hospitalizations and deaths. Half of the adults hospitalized with the flu have CVD, and the risk of a first heart attack is six times higher after Contracting the flu.

More research is needed to assess the protective effects against coronavirus of existing non-COVID-19 vaccines and to study the main immunological mechanisms.

However, in favor of the flu vaccine, both flu and COVID-19 diseases can harm the heart and lungs, and the flu vaccine can reduce this risk. Moreover, the flu vaccine will reduce the number of flu-related hospitalizations and reduce the burden on the health system during the coronavirus pandemic.

Sources

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