Published in IJCP
Can the Concept of a Universal Influenza Vaccination Minimize the Severity of COVID-19?
November 18, 2020 | Kiran Bahrus, Debasis Basu
In view of the uncertainty of when the coronavirus vaccine will finally hit the market and how it is going to yield that protection in terms of efficacy, it is time that we think beyond what is “more than the vaccine”. “It is about vaccination” at large. Influenza vaccination is now being extensively talked about as one of the public health measures to cushion the other epidemic, this current coronavirus outbreak.
Keywords: COVID-19, influenza vaccination
As of July 11, 2020, coronavirus disease 2019 (COVID-19) has been confirmed in 12,322,395 people globally, with a case mortality rate of approximately 4.5%.1 It is well appreciated that COVID-19 mortality rate is higher in the elderly and in those with pre-existing chronic comorbidities like diabetes and cardiovascular disease (CVD), just like seasonal influenza confers increased morbidity and mortality to them.2 Annual influenza vaccination has been routinely recommended for this population since over a decade to battle it out but till date, the rate of the practice of vaccination is abysmally low. Co-infections, seasonal influenza A and B, are being increasingly reported in COVID-19 patients.3,4 The absolute risk reduction from the vaccine was 2- to 4-fold higher in the elderly population with chronic comorbidities compared to the healthy population of the same age group, despite a poor match between the vaccine and circulating strains,5 and also with a low (10%) vaccine effectiveness rate.6
Effectiveness of the vaccine
The vaccine has been shown to be effective at reducing the rate of hospitalization from pneumonia and mortality in elderly people with chronic lung diseases.7 Interestingly, an inverse relationship between influenza vaccine coverage in adults aged between 18 and 64 years and influenza-related illness in the older population (≥65 years) has been observed due to reduced transmission in the community.8 A conjecture is derived that there is a reduction in the complications and deaths associated with COVID-19 when the rate of both acute and chronic respiratory comorbidities in high-risk populations are reduced. Live-attenuated influenza vaccines, by boosting the innate immunity9 may provide transient protection against COVID-19 which is notoriously known to suppress innate immune response,10 thereby reinforcing that vaccination could be beneficial to society at large.
In a study on 92,664 patients from Brazil, inactivated trivalent flu shot also offered protection from getting severe COVID-19. The mortality in the nonimmunized group rose from about 14% in the 10 age group to 84% among those aged 90 years, but lower in all age groups in the immunized group, with the risk being 17% lower in the 10-19 years age group and 3% less in those aged 90 years. Those receiving a recent influenza vaccine experienced on average 8% lower odds of needing intensive care treatment and 18% lower odds of requiring invasive respiratory support.11
Considering age only as a parameter, flu vaccination was associated with a 35% reduction in the mortality among COVID-19 patients. When compared with results of patients getting care at the same healthcare facility, the odds of dying of COVID-19 was found lower by 18%.
Another study on the elderly population in the US showed that for every 10% increase in influenza vaccination, flu shot can reduce mortality by 20% when taken before the onset of COVID-19 and about 27% when the vaccine was given after the onset of COVID-19. Overall, with a 10% increase in vaccination coverage, there was a 28% decrease in the rate of mortality from COVID-19.12
Memory T cells induced by previous pathogens can drive the susceptibility to, and the clinical severity of, subsequent infections.13 Flu virus specifically impairs the ability of T cells to kill virus-infected cells; hence it impairs a person’s immune system to fight against other pathogens, including the COVID-19. Unvaccinated people are at risk of persistent viral infections that decline their T cells diversity, in a way suppressing their immune system. T cells diversity helps fight infections better as it provides a bigger pool of T cells to fight against a new pathogen and it also provides more flexible T cells receptors to fight the pathogen even if it mutates.
Hence, the vaccination promises to boost the immunity. In Italy, it was found that people who took a quadrivalent flu vaccine had a lower death rate from COVID-19. However, this kind of response is more likely in a live-attenuated vaccine, not in an inactivated vaccine. This study also states that both severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19 and the flu virus are RNA viruses for one and they both have similar pathogenesis and transmission. Even though influenza and SARS-CoV-2 display only limited nucleotide sequence similarity, overall CD8+ T-cell epitopes with modest sequence resemblance seem plausible in respect to viral structure, transmission and pathogenic mechanisms, and their binding to viral RNA can then trigger suitable inflammatory and antiviral responses.
A flu shot can be either a live-attenuated vaccine or an inactivated vaccine. The former is given to only healthy people (excluding pregnant women) in the age group of 2-49 years, while the latter can be given to anyone above the age of 6 months (https://www.euro.who.int/en/health-topics/communicable-diseases/influenza/vaccination/types-of-seasonal-influenza-vaccine). An inactivated vaccine does not induce virus-specific T cells in a person and so this drawback of this vaccine may be coming handy now in protecting against COVID-19. Besides the cross-reactivity effect, the anti-flu immune responses can induce bystander immunity14 that is expected to nonspecifically augment immunity against other viral infections, such as SARS-CoV-2. Furthermore, influenza vaccination itself would generate sustained immunity that overall enhances immunity against SARS-CoV-2. As there is evidence of cross-reactivity between flu and SARS-CoV-2, it may be concluded that flu-induced bystander immunity has more of beneficial effects to COVID-19 than those suggested by measles, mumps and rubella (MMR) and bacillus Calmette-Guérin (BCG) vaccines.15,16
Another study conducted in Australia evaluated the immune responses in the blood from a patient with COVID-19 with mild illness.17 They looked at the cellular and humoral immune responses at different time points during the infection, i.e., before, during and after resolution of the disease. Their longitudinal analysis showed a robust immune response across different cell types associated with clinical recovery. Accordingly, a link is suggested between the quality of the immunity and recovery from COVID-19, at least in part, in patients with mild symptoms. A hypothesis was presented that the immunity against prior influenza infection, at least in part, also developed immunity against SARS-CoV-2. This hypothesis is supported by the previous studies showing cross-reactivity of immunity between flu and coronavirus due to the similarity in their structures.18,19
Furthermore, influenza vaccination itself would evoke sustained immunity that would enhance immunity against SARS-CoV-2. As different strains of coronavirus can develop because of mutations and natural selection besides recombination, a directed stable vaccine is very unlikely. Till then, it is recommended that flu vaccine be used, at least in part, as a bystander adjuvant to minimize the severity of COVID-19 disease due to the safety profile of flu vaccine in adults.
Yet, despite the availability of safe flu vaccines, influenza vaccine hesitancy, i.e., low influenza vaccine uptake rates, both in general public and even within specific risk groups remain a significant challenge throughout the globe and contribute to the burden of disease, especially in the elderly.20-23
At this point in the pandemic, there is inadequate evidence about the effectiveness of antibody-mediated immunity to guarantee the accuracy of an “immunity passport” or “risk-free certificate”. People who have received a positive test result may assume that they are immune to a second infection and, therefore, ignore public health advice. The use of such complacent certificates may heighten the risks of continued transmission.24 Governments should seriously consider promoting flu vaccination at this time as a bystander adjuvant to minimize the severity of COVID-19 disease.25 Anticipating the possibility of a deadly potential of a global influenza-COVID-19 co-infection,26 it has been suggested that the influenza vaccination could be used to indirectly control COVID-19.25,27
An almost universal uptake of this influenza vaccination across continents may engender herd immunity and thus protect even those in whom the vaccine may be ineffective to cope better with COVID-19 complications as lockdowns will inevitably be relaxed.28 To meet the urgent need for a coronavirus vaccine, a new pandemic vaccine development paradigm has been proposed that compresses the development timeline from 10-15 years to 1-2 years.29 Slowing the spread of the COVID-19 cases will significantly reduce the strain on the healthcare system of the country by limiting the number of people who are severely sick by COVID-19 and need hospital care.30 To simplify the primary clinicians’ work, may the influenza vaccine be targeted for the fall season this year, be it for a larger group of the entire global population as another new wave of COVID-19 is predicted to hit in parallel with the start of the influenza season.
- World Health Organisation. Coronavirus disease (COVID-19): Situation Report–173. WHO, July 11, 2020. Available at: https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200711-covid-19-sitrep-173.pdf?sfvrsn=949920b4_2
- Keilman LJ. Seasonal influenza (flu). Nurs Clin North Am. 2019;54(2):227-43.
- Konala VM, Adapa S, Gayam V, Naramala S, Daggubati SR, Kammari CB, et al. Co-infection with influenza A and COVId-19. Eur J Case Rep Intern Med. 2020;7(5):001656.
- Xing Q, Li G, Xing Y, Chen T, Li W, Ni W, et al. Precautions are needed for COVID-19 patients with coinfection of common respiratory pathogens. 2020.02.29.20027698.
- Hak E, Nordin J, Wei F, Mullooly J, Poblete S, Strikas R, et al. Influence of high-risk medical conditions on the effectiveness of influenza vaccination among elderly members of 3 large managed-care organizations. Clin Infect Dis. 2002;35(4):370-7.
- Fry AM, Kim IK, Reed C, Thompson M, Chaves SS, Finelli L, et al. Modeling the effect of different vaccine effectiveness estimates on the number of vaccine-prevented influenza-associated hospitalizations in older adults. Clin Infect Dis. 2014;59(3):406-9.
- Nichol KL, Baken L, Nelson A. Relation between influenza vaccination and outpatient visits, hospitalization, and mortality in elderly persons with chronic lung disease. Ann Intern Med. 1999;130(5):397-403.
- Taksler GB, Rothberg MB, Cutler DM. Association of influenza vaccination coverage in younger adults with influenza-related illness in the elderly. Clin Infect Dis. 2015;61(10):1495-503.
- Chumakov K, Benn CS, Aaby P, Kottilil S, Gallo R. Can existing live vaccines prevent COVID-19? Science. 2020;368(6496):1187-8.
- Zheng M, Gao Y, Wang G, Song G, Liu S, Sun D, et al. Functional exhaustion of antiviral lymphocytes in COVID-19 patients. Cell Mol Immunol. 2020;17(5):533-5.
- Fink G, Orlova-Fink N, Schindler T, Girisi S, Ferrer AP, Daubenberger C, et al. Inactivated trivalent influenza vaccine is associated with lower mortality among Covid-19 patients in Brazil. medRxiv preprint. 2020.06.29.201425052.
- Zanettini C, Omar M, Dinalankara W, Imada EL, Colantuoni E, Parmigiani G, et al. Influenza vaccination and COVID-19 mortality in the USA. Version 1. medRxiv. 2020.06.24.20129817.
- Welsh RM, Selin LK. No one is naive: the significance of heterologous T-cell immunity. Nat Rev Immunol. 2002;2(6):417-26.
- Horns F, Dekker CL, Quake SR. Memory B cell activation, broad anti-influenza antibodies, and bystander activation revealed by single-cell transcriptomics. Cell Rep. 2020;30(3):905-13.e6.
- Salman S, Salem ML. The mystery behind childhood sparing by COVID-19. Int J Cancer Biomed Res. 2020;5(1):11-3.
- Salman S, Salem ML. Routine childhood immunization may protect against COVID-19. Med Hypotheses. 12020;40:109689.
- Thevarajan I, Nguyen THO, Koutsakos M, Druce J, Caly L, van de Sandt CE, et al. Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19. Nat Med. 2020;26(4):453-5.
- Zheng J, Perlman S. Immune responses in influenza A virus and human coronavirus infections: an ongoing battle between the virus and host. Curr Opin Virol. 2018;28:43-52.
- Zeng Q, Langereis MA, van Vliet AL, Huizinga EG, de Groot RJ. Structure of coronavirus hemagglutinin-esterase offers insight into corona and influenza virus evolution. Proc Natl Acad Sci U S A. 2008;105(26):9065-9.
- MacDonald NE; SAGE Working Group on Vaccine Hesitancy. Vaccine hesitancy: Definition, scope and determinants. Vaccine. 2015;33(34):4161-4.
- Yeung MP, Lam FL, Coker R. Factors associated with the uptake of seasonal influenza vaccination in adults: a systematic review. J Public Health (Oxf). 2016;38(4):746-53.
- World Health Organization. (2015). The Global Action Plan for influenza vaccines: report of the tenth meeting of the Advisory Group of the WHO Global Action Plan for Influenza Vaccines. World Health Organization. Available at: https://apps.who.int/iris/handle/10665/182733
- Mereckiene J, Cotter S, Weber JT, Nicoll A, D'Ancona F, Lopalco PL, et al; VENICE project gatekeepers group. Influenza A(H1N1)pdm09 vaccination policies and coverage in Europe. Euro Surveill. 2012;17(4):20064.
- World Health Organization. “Immunity passports” in the context of COVID-19: Scientific brief. April 24, 2020. World Health Organization. Available at: https://apps.who.int/iris/handle/10665/331866.(2020)
- Salem ML, El-Hennawy D. The possible beneficial adjuvant effect of influenza vaccine to minimize the severity of COVID-19. Med Hypotheses. 2020;140:109752.
- Antony SJ, Almaghlouth NK, Heydemann EL. Are co-infections with COVID-19 and influenza low or underreported? An observational study examining current published literature including three new unpublished cases. J Med Virol. 2020;92:2489-97.
- Osterhaus ADME. Influenza and RSV in a COVID-19 World. The First ESWI Webinar 11 June 2020. Available online: https://eswi.org/eswi-tv/influenza-and-rsv-in-a-covid-19-world-full-webinar/. Accessed Sept 12, 2020.
- Grech V, Borg M. Influenza vaccination in the COVID-19 era. Early Human Development. 2020;148:105116.
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- Vellingiri B, Jayaramayya K, Iyer M, Narayanasamy A, Govindasamy V, Giridharan B, et al. COVID-19: A promising cure for the global panic. Sci Total Environ. 2020;725:138277.