A new study involving more than 92,000 COVID-19 patients in Brazil shows that the odds of serious illness, ventilatory support requirement, and death are reduced with a trivalent recent flu shot. This seems to indicate that these vaccines should be used as widely as possible to reduce the risk of severe COVID-19, especially among high-risk groups. The study is published on the prepress server. medRxiv * in June 2020.
Novel SARS-CoV-2 coronavirus Colored scanning electron micrograph of a cell (blue) heavily infected with SARS-CoV-2 virus particles (red), isolated from a patient sample. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Credit: NIAID
The situation of COVID-19 in Brazil
Brazil has seen a massive increase in the number of COVID-19 cases in recent weeks. With the outbreak apparently under control in most temperate zone countries, with the exception of the United States, the pandemic is still spreading in countries south of these latitudes. Elderly and sick people bear the brunt of the pandemic with conditions such as diabetes mellitus, obesity, and cardiovascular disease.
Today, non-pharmaceutical interventions are the main route of challenge to the pandemic, including regional or national blockades, restriction of public mobility, and the use of hand sanitizers and face masks. This has caused the greatest global economic impact since World War II, mainly due to the absence of effective drug treatment or vaccine.
Imminent flu season in southern latitudes
Many of the countries now affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are approaching winter, and this may cause seasonal increases in influenza cases. These cause up to 650,000 deaths each year, in the temperate zone. Influenza vaccines are available and recommended, but remain underused due to concerns about their safety and effectiveness. Misinformation about its connection to adverse outcomes in COVID-19 patients has also contributed to its underuse.
The Study: Does Flu Vaccination Benefit COVID-19 Patients?
The current study examines the results in more than 92,000 patients with COVID-19 in Brazil, who have recently received and have not received flu shots. About 84% of these patients had tested positive for the virus by RT-PCR. The rest were clinically diagnosed. About 57% were men, with a group median age of 59 years.
Most of the people belonged to the age group of 60 to 69 years, and 37% required intensive care at some point, while 23% finally received mechanical ventilation. About 47% of the patients died. The mortality rate, which is already high, goes from approximately 15% among children under 10 years old to 83% among those over 90 years old.
About 66% already had cardiovascular disease, while 55% had diabetes mellitus. About 11% were obese or had neurological disease, and 12% had kidney disease.
About a third of these patients had been vaccinated against influenza during the last immunization cycle, mainly among those over 60, and the best educated.
The situation of the flu vaccine in Brazil
The seasonal influenza season in Brazil is at its peak among the 18th and 19th weeks, falling in April and May, while later, at 25th to 27th weeks, in more southern states. This year’s annual flu shot campaign was held a month ahead of schedule in anticipation of the next COVID-19 spike. It is aimed at older patients and health workers first, then patients with chronic health conditions and other workers in direct and prolonged contact with the public. Children and other high-risk groups are immunized in phase 3. The current round used the WHO recommended trivalent vaccine.
All groups had less than 50% coverage with the flu shot, and the highest coverage was among children and adults age 60 and older. Approximately two out of three individuals were vaccinated in the current campaign, but about 7% after they reported COVID-19 symptoms.
Low mortality after flu vaccination
The researchers found that in the unimmunized group, COVID-19 mortality increased from about 14% in the under-10 age group to 84% among people 90 and older. However, mortality was lower in all age groups in the immunized group, with a 17% lower risk in the 10 to 19-year-old group and 3% lower in those aged 90 and older.
When the relationship between the flu shot and age was explored, there was a greater reduction in the odds of dying of COVID-19 by more than a third, to 35%. The researchers then analyzed mortality rates between vaccinated and unvaccinated patients in the same facility. They found that COVID-19’s odds of dying are still 18% lower.
They also adjusted for multiple health variables and for socioeconomic variables, but found that this did not significantly change the magnitude of the positive association.
When only patients with a positive diagnosis proven by RT-PCR are considered, the association remains significant. As shown in previous studies, the presence of obesity and lung disorders, as well as kidney and kidney disorders, had a higher risk of death, but people with asthma had a lower risk.
Decreased odds of poor outcome after flu vaccination
Patients who received the flu shot were 8% less likely to need intensive care and 20% less likely to need respiratory assistance. Overall, they found that people vaccinated in the current round were protected, but not those vaccinated before. Those who were vaccinated before developing COVID-19 symptoms had a 20% reduction in the odds of mortality. Still, if administered after initiation, the vaccine was associated with a 27% reduction in the odds of death, although the difference is not significant.
In the last group, protection was more significant for those younger than 60 years when it was administered before the onset of COVID-19 symptoms.
Protection mechanism with influenza vaccine
The study shows that influenza vaccines do not increase the risk of an adverse outcome after COVID-19, but they do have a protective effect. This could be through various mechanisms. One of them is the potential prevention of influenza coinfection with COVID-19, but this is rare, since it is found in only 30 cases among the large study population.
The second explanation is the vaccine’s effect of eliciting long-lasting protective neutralizing antibodies and T-cell-specific responses. These could cross-react with SARS-CoV-2. This is also unlikely due to the great diversity among influenza viruses, and also due to the lack of protection conferred by previous rounds of influenza vaccines compared to the current campaign implementation.
The most likely mechanism, therefore, is a vaccine-induced change in innate immunity. Immune memory cells are found in the innate immune compartment and tissue-resident stem cells. These can be activated by natural or artificial antigen challenges. As a result, these innate immune cells will defend the body against multiple pathogens, including those that are not targeted by the vaccine.
Implications and recommendations
Previous studies have shown that after subjects first received BCG or influenza vaccines, and then peripheral blood mononuclear cells were restimulated with unrelated antigens, a wide range of cytokines were released, with dominant secretion of TNF-α e IL-6. Similarly, live vaccines against measles, smallpox, and polio also resulted in significant protection against other pathogens. All this contributes to a significant reduction in mortality rates after vaccination.
The researchers suggest: “Given the high similarities of SARS-CoV-2 and influenza viruses with respect to viral structure, transmission, and pathogenic mechanisms, it seems plausible that both viruses are detected by similar pattern recognition receptors or identical. Its binding to viral RNA can trigger adequate inflammatory and antiviral responses. “
This is supported by research showing that influenza virus single-stranded RNA binds to the Toll-like receptor (TLR), and this elicits both humoral and T-cell immune responses, as well as innate immune responses due to priming by increased cytokines. launching. This results in naturally occurring killer (NK) cells, which can then be activated by other viruses like SARS-CoV-2 as well.
This hypothesis is supported by evidence of less protection in older patients, which is known to be the case with the flu vaccine, since the innate immune system may become less active with advancing age.
As for the improved recovery after influenza vaccination, even after the onset of COVID-19 symptoms, this may be explained by the resulting increase in the rapid and efficient elimination of the virus, which prevents its spread to lower areas of the lung. Second, it could reduce the intensity of the unregulated cytokine storm observed in progressive, often fatal COVID-19. Therefore, future research should focus on these off-target effects to help discover the nature and duration of protection offered by the flu vaccine, both systemically and in the respiratory tract.
The study concludes: “In the absence of a Covid-19 vaccine and without a well-established treatment to prevent disease progression, induction of trained immunity that exerts beneficial and off-target effects could be a fruitful way to improve the results of Covid-19. “Governments should seriously consider promoting flu vaccination at this time in view of the many benefits, as reducing the number of severe cases of COVID-19 will help ease the strain on the health system and allow that the sickest patients receive adequate care.
*Important news
medRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered conclusive, guide clinical practice / health-related behavior, or treated as established information.
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