1. Introduction
Severe Acute Respiratory Syndrome Coronavirus 2 (Sars-Cov-2 virus), since its onset, has been accompanied by an overall case fatality ratio of 2.3% and an attack rate varying between 4.6% to 49.56% (Shah 2020; Wiersinga 2020). With progressive research on the origins and nature of Sars-Cov-2 infection, we gain a better understanding of associated risk factors and their likeness to influenza infection.
Despite the current rollout of the Sars-Cov-2 vaccine, many regions across the globe, especially Southeast Asia and Africa, are battling the virus with minimal vaccine access (George 2021). However, taking into account the structural symmetry between the influenza and the SARS-CoV-2 viruses, we observe something important. We see the influenza vaccine as a valuable resource to fill the gaps.
A 2020 study revealed significant correlations between specific comorbidities and the severity of SARS-CoV-2. It found that 10.5% of cases with severe outcomes involved cardiovascular disease (CVD), 37.3% involved diabetes, 8.3% involved chronic obstructive pulmonary diseases (COPD), 55.4% involved hypertension, and 8.1% involved cancer (Sanyaolu 2020). These high-risk patients do not include those children who are suffering from pre-existing medical conditions such as cardiovascular disease, Pulmonary Tract Infections, and asthma. (Thindwa 2020) Many countries are yet to approve vaccines for these risk groups, both children and adults. The flu vaccine can, however, be used to mitigate Sars-Cov-2 infections and reduce the risk of mortality.
2. Methods
This paper is based on previous studies involving, but not limited to, retrospective studies, meta-analyses, journal articles, and randomized controlled trials.
2.1 Search Strategy
The review involved searching electronic databases, including PubMed and ScienceDirect, for relevant studies using a pre-defined search strategy. For this research, the mortality rate was chosen as a severity factor, representing how critical or life-threatening a case is.
2.2 Search Terms
The keywords used for searching in the database included: Influenza, Vaccine, Efficacy, and Sars-Cov-2. These terms were derived from previous reviews and informatics experts interested in vaccine research.
2.3 Study Eligibility Criteria
The inclusion and exclusion criteria of the research articles were carefully established to guide the selection process for this study. A younger population could not be selected due to the lack of relevant literature. Furthermore, the Sars-Cov-2 vaccine chosen for this comparison was restricted to mRNA vaccines due to a limited number of original studies focusing on other types of vaccines. The rate of mortality was chosen as a severity factor for this research.
3. Molecular Comparison of Sars-Cov-2 and the Influenza
Sars-Cov-2 and influenza, both retroviruses, use RNA as their genetic material and replicate in reverse to the Central Dogma (Abdelrahman, 2020). Previous studies have found that Sars-Cov-2 and Influenza shared similar symptoms such as fever, fatigue, dry cough, dyspnea, and pulmonary infiltration (Manzanares-Meza, 2020) There are also cases of acute respiratory distress syndrome (ARDS) prevalent in higher-risk groups.
However, patients suffering from Sars-Cov-2 have additional complications such as blood clots, Multisystem Inflammatory Syndrome in Children (MIS-C), and MIS-A in adults (Manzanares-Meza, 2020).
3.1 Cellular Comparison of the two viruses
Both Influenza (Orthomyxoviridae family) and SARS-CoV-2 (Orthocoronaviridae family) are single-stranded RNA viruses. Influenza A’s genome is around 13.5 kb while SARS-CoV-2’s is about 30 kb, making it one of the largest known RNA viruses. Both viruses encode polyproteins that undergo proteolysis to form functional proteins, including those crucial for replication. SARS-CoV-2’s larger genome enables it to encode more proteins, potentially enhancing its infectivity. SARS-CoV-2’s genome is distinct from SARS-CoV, sharing less than 80% nucleotide identity (ASM.org, 2020). Notably, Sars-Cov-2 spreads more easily than the flu. Influenza’s lack of proofreading leads to high mutation rates, mainly in surface proteins like hemagglutinin (H) and neuraminidase (N), targeted by neutralizing antibodies. Evolution in Influenza relies on mutations in these proteins, termed antigenic drift. SARS-CoV-2 differs as it has a more accurate copying mechanism (Manzanares-Meza, 2020).
3.2 Mechanism of Infection
Both Influenza and SARS-CoV-2 share a similar infection mechanism, duration of illness, complications, and mode of spread. They both target and invade upper respiratory tract epithelial cells and primarily and primarily spread through direct contact.
The Influenza virus replicates in the respiratory tract’s epithelium. Its viral cycle begins with HA binding to sialic acid on target cell glycoproteins. After internalization, conformational changes in HA trigger fusion between the viral envelope and endosome membrane. Viral components enter the cell nucleus, initiating replication and transcription (Sriwilaijaroen, N., 2012)
SARS-CoV-2 utilizes the angiotensin-converting enzyme 2 as its entry receptor (Figure 1). The S protein has S1 and S2 domains. S1 binds to the cell receptor, while S2 facilitates viral membrane-cell membrane fusion (Manzanares-Meza, 2020).
Mechanism of Infection of Sars Cov 2
3.3 Uptake of the Sars-Cov-2 and the Flu Vaccine
Currently, on a global scale, there are countless types of vaccines available for both influenza and the Sars-Cov-2 vaccines. These vaccines can be categorized into several types. Attenuated vaccines utilize live viruses or bacteria. Inactivated vaccines employ weakened forms of the virus or bacteria. Subunit vaccines contain only parts of the virus, and mRNA vaccines use messenger RNA to prompt an immune response.
Pfizer and Moderna, manufacturers of the two most widely used SARS-CoV-2 vaccines, employ mRNA to stimulate the immune response. In contrast, most flu vaccines use an inactivated virus produced from eggs. In most cases of the influenza vaccine, the virus is inactivated, harvested in eggs, and then made into vaccines (CDC, 2021)
Sars-Cov-2 and flu share similar initial immune responses due to overlapping symptoms, potentially reducing severity through quick innate immune reactions. Herein, innate immunity is the body’s first line of defence, responding quickly and non-specifically to pathogens, whereas adaptive immunity develops a targeted response to specific threats over time (Zanettini, 2020; Del Riccio, 2020)
4. Sars-Cov-2 Infection and the Influenza Vaccine
In China, among 44,500 Sars-Cov-2 cases (early 2022), 80% were mild, 14% had dyspnea/hypoxia, and 5% were critical with respiratory/systemic failure. During the same time period, in the US, 14.2% required ICU care, 12.2% required ventilators, and 21% faced mortality (Manzanares-Meza, 2020)
The influenza vaccine may reduce mortality, especially in South Asia, Africa, and Latin America. Global vaccine equity, highlighted by the World Health Organisation (WHO), is vital for pandemic control. Low-income nations possess more influenza vaccines than Sars-Cov-2 vaccines. Inactivated Influenza varies in effectiveness, from roughly 20% in seasons with a poor match to the circulating strains to up to 60% closer matched seasons (Thindwa, 2020). But despite the variability in effectiveness, the Influenza shot may be crucial in various contexts.
4.1 Infection Rates
Studies have linked lower SARS-CoV-2 infection rates to influenza vaccination, though this may not necessarily indicate a direct correlation. Potential confounding factors, such as the likelihood that individuals who receive flu vaccines might also practice more COVID-19 prevention behaviors like masking and avoiding crowds, were not controlled for in these studies. Therefore, while the flu vaccine may play a role in reducing the risk of COVID-19, further research is needed to explore potential mechanisms and collect data on personal health behaviors. In a study of 27,201 patients, influenza vaccine recipients showed significantly reduced odds of Sars-Cov-2 contraction (OR: 0.58, 95% CI: 0.46–0.73; P < .001). Those vaccinated also had lower hospitalization, mortality, ICU need, stay length, and ventilation rates (Conlon, 2021).
Similar outcomes were found in another study conducted by researchers in Taiwan: those unvaccinated had higher hospitalization risk (2.4 times) and home-to-ICU transfer likelihood (3.3 times). Cumulatively, evidence indicates influenza vaccination could guard against Sars-Cov-2 and its effects. Further studies are needed to confirm these findings and understand the underlying mechanisms of influenza vaccines in the case of Sars-Cov-2 infections (Hsu, 2020).
4.2 Mortality and Morbidity Rates
Several studies have investigated the effectiveness of the influenza vaccine in reducing morbidity and mortality rates associated with influenza infection. In one study, individuals who received the flu vaccine and contracted the virus were found to be less likely to experience severe illness and require mechanical ventilation (odds ratio, 0.45, 95% CI 0.27–0.78; P = 0.004). Infected individuals who had received the vaccine also had a shorter hospital stay (risk ratio, 0.76, 95% CI 0.65–0.89; P < .001) compared to those unvaccinated (Conlon, 2021).
A literature review covering 100,000+ individuals indicated influenza vaccine effectiveness against Sars-Cov-2 outcomes up to 120 days post-vaccination, notably in older adults and those with comorbidities (Del Riccio, 2020). These findings suggest that prioritizing influenza vaccination efforts for vulnerable populations could have significant benefits (Del Riccio, 2020; Conlon 2021; Hsu 2020)
4.3 Cardiovascular Protection
Influenza vaccination, known to lower flu-related risks, is emerging as a preventive measure against adverse cardiovascular outcomes. Growing evidence suggests its potential benefits extend beyond respiratory health, notably reducing heart attack and stroke risks in those with and without pre-existing cardiovascular disease (CVD). Given these supportive findings, further investigation is warranted into these cardioprotective effects.
Additionally, the elderly and those with chronic conditions, including CVD, are at high risk for severe outcomes from influenza and Sars-Cov-2. However, limited access to Sars-Cov-2 vaccines persists. Immunosenescence, coupled with chronic illness, can compromise vaccine effectiveness.
Sars-Cov-2 exacerbates mortality risk in CVD patients due to increased clotting propensity. Healthcare workers must prioritize vaccination to counter these challenges. Several randomized controlled trials suggest influenza shots guard against cardiovascular events. A 2013 meta-analysis across 6 trials found lower composite cardiovascular event risk with influenza vaccination (vaccine 2.9% vs control 4.7%; RR: 0.64; 95% CI: 0.81% to 2.67%; p = 0.003). (Udel, 2013)
Cardioprotective effects stem from infection prevention and immune- inflammatory system interactions. Influenza vaccine-induced antibodies could stabilize atherosclerotic plaques and enhance nitric oxide production via bradykinin 2 receptor interaction, thereby improving circulation and myocardial function. Nitric oxide is a potent neurotransmitter that improves circulation, regulates myocardial contractility, limits leukocyte adhesion to the endothelium, and prevents platelet activation (Behrouzi, 2020).
Furthermore, influenza vaccination may have important implications for protecting high-risk CVD patients from superimposed secondary infections such as influenza (Del Riccio 2020; Islam 2020)
5. Administration of the Flu Vaccine
The flu vaccine has been around for many decades. But, with the rise of the Sars-Cov-2 pandemic, vaccine implementation and administration have taken a new form.
5.1 Effect of the Flu Vaccine on Covid Infections
Survey-based and peer-reviewed studies propose that the effectiveness of influenza vaccines in reducing Sars-Cov-2 severity relies on dose administration and dosing intervals (Hsu, 2020). Optimal efficacy was observed with a minimum 2-week gap between vaccine administration. Some indications suggest benefits from influenza vaccine boosters in Sars-Cov-2 protection, although these claims await scientific confirmation. Reports also highlight that divalent (two-strain) influenza vaccines are more effective than monovalent (one-strain) counterparts. The wider strain coverage of divalent vaccines likely extends to Sars-Cov-2 protection as well (Del Riccio 2020; Conol 2021)
5.2 Availability of Vaccines
Significant shortages of Sars-Cov-2 vaccines persist in Southeast Asia, Africa, and Latin America. WHO data reveals low vaccination rates across Africa (2–8%), exacerbated by expired vaccines. Despite abundant stocks, many doses remain unused, even in developing nations. This suggests a correlation where the limited availability of vaccines leads to delayed distribution and administration, causing many doses to expire before use, even in countries with abundant stocks. Consequently, these expired vaccines contribute to the high number of unused doses in developing nations. In the US, 15 million Sars-Cov-2 vaccines were discarded (NBCUniversal News Group 2021) Similar situations apply to types of flu vaccines, like Flucelvax, in sub-Saharan Africa. Some Latin American countries, including Costa Rica, Nicaragua, and Panama, report production and shipment-related shortages of both flu and Sars-Cov-2 vaccines. Developed nations’ reluctance to share their vaccine stock and difficulty in maintaining donations aggravates the shortage.
Flu vaccines generally have a longer shelf life compared to mRNA SARS-CoV-2 vaccines, which is beneficial for broader distribution. For instance, some flu vaccines, like Flublok, have been reported to have a shelf life of up to 9 months according to FDA extensions. In contrast, mRNA vaccines, such as those for SARS-CoV-2, typically have a much shorter shelf life and require stringent storage conditions like ultra-cold temperatures. This longer shelf life of flu vaccines facilitates easier and more effective distribution, especially in settings where cold chain logistics are challenging (World Health Organization., n.d)
5.3 Impact of Covid on Flu Vaccine Uptake
Initially, Sars-Cov-2 led to reduced flu vaccine administration. However, uptake improved in 2020–2021. In New York City, late 2020 saw a 9% rise in flu vaccination, with adolescents up by 13% and older adults, those above the age of 60 by 9.5%. Conversely, Liberia experienced a 4.3% decline in vaccination rates, highlighting the urgent need for enhanced vaccine equity, particularly in low-resource settings. This decline serves as a stark reminder of the disparities in vaccine distribution and access, emphasizing the critical importance of ensuring equitable vaccine availability worldwide to effectively combat global health threats (NBCUniversal News Group, 2021; World Health Organisation n.d)
6. Limitations and Conclusion
In challenging pandemic circumstances, the flu shot presents a viable alternative to the Sars-Cov-2 vaccine, particularly in areas with constrained healthcare infrastructure or resources. This can include regions with inadequate refrigeration capabilities for storing mRNA vaccines, areas with limited access to healthcare facilities, or communities that face logistical challenges in vaccine distribution. Several study findings suggest the flu shot, while not a replacement for the Sars-Cov-2 vaccine, may mitigate Sars-Cov-2 transmission and risk factors, especially in low-income countries with restricted Sars-Cov-2 vaccine access. Prioritizing influenza vaccination is essential for these regions, considering its ease of production, longer shelf-life, and broader accessibility.
This paper, however, does not suggest that the influenza vaccine should replace the SARS-CoV-2 vaccine. It’s important to note that, the flu vaccine and SARS-CoV-2 vaccine target different viruses and are formulated to protect against specific viral strains prevalent in their respective flu and SARS-CoV-2 seasons. There is a lack of direct evidence linking influenza vaccination to a reduced incidence of SARS-CoV-2 or its complications. Future studies, particularly randomized controlled trials, are therefore necessary to explore any potential protective effects of the flu vaccine against SARS-CoV-2-associated mortality. The effectiveness of the flu vaccine can also vary significantly from year to year, depending on the match between the vaccine strains and the circulating strains. This variability can affect the reliability of any inferred protective effects against SARS-CoV-2. Additionally, given the evolving nature of the Sars-Cov-2 pandemic, timely research is crucial to better understand the disease and a subsequent cure.
Low-income countries should prioritize vaccinating their populations with the influenza vaccine as a means of controlling the spread of Sars-Cov-2 until more efficient Sars-Cov-2 vaccines become widely available. Disparities between developed and developing nations persist, reinforcing the urgency for equitable access to vaccines.
Acknowledgment
I am immensely indebted to IRI-NC for giving me my very first research experience and I would like to thank everyone at IRI for giving me this amazing experience. I offer immense thanks to Angella Parra, the Assistant Director of IRI, for accommodating my request for leave and for her support throughout the program. I would also like to thank Irma Oomen for her support while applying to the program. I am largely indebted to Dr. Malkin for his invaluable insights, guidance, and suggestions throughout this project. Also, I relay immense thanks to my mentor Emma Joo for guiding me at every step, supporting me with new ideas, and helping me navigate different papers. This paper might not have been possible without her support.
Author contribution statement
Rimmo Loyi Lego (RL) conceptualized and designed the study, collected and analyzed the data, and wrote the manuscript.
Prof Robert Malkin (RM) provided overall supervision, and guidance, and contributed to manuscript editing. All authors have read and approved the final manuscript.
References
1. Abdelrahman, Z., Li, M., & Wang, X. (2020). Comparative review of SARS-COV-2, SARS-COV, MERS-COV, and influenza A respiratory viruses. Frontiers in Immunology, 11. https://doi.org/10.3389/fimmu.2020.552909https://doi.org/10.3389/fimmu.2020.552909
2. Behrouzi, B., Araujo Campoverde, M. V., Liang, K., Talbot, H. K., Bogoch, I. I., McGeer, A., Fröbert, O., Loeb, M., Vardeny, O., Solomon, S. D., & Udell, J. A. (2020). Influenza vaccination to reduce cardiovascular morbidity and mortality in patients with COVID-19: JACC State-of-the-Art Review. Journal of the American College of Cardiology, 76(15), 1777–1794. https://doi.org/10.1016/j.jacc.2020.08.028https://doi.org/10.1016/j.jacc.2020.08.028
3. Centers for Disease Control and Prevention. (2021, November 18). Key facts about the seasonal flu vaccine. https://www.cdc.gov/flu/prevent/keyfacts.htm#:~:text=How%20do%20flu%20vaccines%20work,infection%20with%20circulating%20influenza%20viruseshttps://www.cdc.gov/flu/prevent/keyfacts.htm#:~:text=How%20do%20flu%20vaccines%20work,infection%20with%20circulating%20influenza%20viruses
4. Conlon, A., Ashur, C., Washer, L., Eagle, K. A., & Hofmann Bowman, M. A. (2021). Impact of the influenza vaccine on COVID-19 infection rates and severity. American Journal of Infection Control, 49(6), 694–700. https://doi.org/10.1016/j.ajic.2021.02.012https://doi.org/10.1016/j.ajic.2021.02.012
5. Del Riccio, M., Lorini, C., Bonaccorsi, G., Paget, J., & Caini, S. (2020). The association between influenza vaccination and the risk of SARS-CoV-2 infection, severe illness, and death: A systematic review of the literature. International Journal of Environmental Research and Public Health, 17(21), 7870. https://doi.org/10.3390/ijerph17217870https://doi.org/10.3390/ijerph17217870
6. George, J. A., Maphayi, M. R., & Pillay, T. (2021). COVID-19 and vulnerable populations in Sub-Saharan Africa. In Advances in Experimental Medicine and Biology (Vol. 1321, pp. 147–162). https://doi.org/10.1007/978-3-030-59261-5_13https://doi.org/10.1007/978-3-030-59261-5_13
7. Hsu, Y. L., Lin, H. C., Wei, H. M., Lai, H. C., & Hwang, K. P. (2020). One benefit of COVID-19 measures in Taiwan is the reduction of influenza infections and severe complications. Influenza and Other Respiratory Viruses, 14(6), 757–758. https://doi.org/10.1111/irv.12778https://doi.org/10.1111/irv.12778
8. Islam, M. R., Hoque, M. N., Rahman, M. S., Alam, A. S., Akther, M., Puspo, J. A., Akter, S., Sultana, M., Crandall, K. A., & Hossain, M. A. (2020). Genome-wide analysis of SARS-COV-2 virus strains circulating worldwide implicates heterogeneity. Scientific Reports, 10(1). https://doi.org/10.1038/s41598-020-70812-6https://doi.org/10.1038/s41598-020-70812-6
9. Manzanares-Meza, L. D., & Medina-Contreras, O. (2020). SARS-CoV-2 and influenza: A comparative overview and treatment implications. Boletín Médico del Hospital Infantil de México, 77(5), 262–273. https://doi.org/10.24875/BMHIM.20000183https://doi.org/10.24875/BMHIM.20000183
10. NBCUniversal News Group. (2021, September 1). 15 million COVID vaccine doses thrown away in the U.S. since March, new data shows. NBCNews.com. https://www.nbcnews.com/news/us-news/america-has-wasted-least-15-million-covid-vaccine-doses-march-n1278211https://www.nbcnews.com/news/us-news/america-has-wasted-least-15-million-covid-vaccine-doses-march-n1278211
11. Sanyaolu, A., Okorie, C., Marinkovic, A., Patidar, R., Younis, K., Desai, P., Hosein, Z., Padda, I., Mangat, J., & Altaf, M. (2020). Comorbidity and its impact on patients with COVID-19. SN Comprehensive Clinical Medicine, 2(8), 1069–1076. https://doi.org/10.1007/s42399-020-00363-4https://doi.org/10.1007/s42399-020-00363-4
12. SARS-COV-2 sequencing data: The devil is in the genomic detail. (n.d.). American Society for Microbiology. Retrieved February 25, 2022, from https://asm.org/Articles/2020/October/SARS-CoV-2-Sequencing-Data-The-Devil-Is-in-the-Genhttps://asm.org/Articles/2020/October/SARS-CoV-2-Sequencing-Data-The-Devil-Is-in-the-Gen
13. Shah, K., Saxena, D., & Mavalankar, D. (2020). The secondary attack rate of COVID-19 in household contacts: A systematic review. QJM: An International Journal of Medicine, 113(12), 841–850. https://doi.org/10.1093/qjmed/hcaa232https://doi.org/10.1093/qjmed/hcaa232
14. Sriwilaijaroen, N., & Suzuki, Y. (2012). Molecular basis of the structure and function of H1 hemagglutinin of influenza virus. Proceedings of the Japan Academy, Series B, Physical and Biological Sciences, 88(6), 226–249. https://doi.org/10.2183/pjab.88.226https://doi.org/10.2183/pjab.88.226
15. Thindwa, D., Garcia Quesada, M., Liu, Y., Bennett, J., Cohen, C., Knoll, M. D., von Gottberg, A., Hayford, K., & Flasche, S. (2020). Use of seasonal influenza and pneumococcal polysaccharide vaccines in older adults to reduce COVID-19 mortality. Vaccine, 38(34), 5398–5401. https://doi.org/10.1016/j.vaccine.2020.06.047https://doi.org/10.1016/j.vaccine.2020.06.047
16. Udell, J. A., Zawi, R., Bhatt, D. L., Keshtkar-Jahromi, M., Gaughran, F., Phrommintikul, A., Ciszewski, A., Vakili, H., Hoffman, E. B., Farkouh, M. E., & Cannon, C. P. (2013). Association between influenza vaccination and cardiovascular outcomes in high-risk patients: A meta-analysis. JAMA, 310(16), 1711–1720. https://doi.org/10.1001/jama.2013.279206https://doi.org/10.1001/jama.2013.279206
17. Wiersinga, W. J., Rhodes, A., Cheng, A. C., Peacock, S. J., & Prescott, H. C. (2020). Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): A review. JAMA, 324(8), 782–793. https://doi.org/10.1001/jama.2020.12839https://doi.org/10.1001/jama.2020.12839
18. World Health Organization. (n.d.). COVID-19 vaccine tracker and landscape. Retrieved March 25, 2022, from https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccineshttps://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines
19. World Health Organization. (n.d.). COVID-19 vaccines. Retrieved March 25, 2022, from https://www.who.int/emergencies/diseases/novel-coronavirus-2019/covid-19-vaccineshttps://www.who.int/emergencies/diseases/novel-coronavirus-2019/covid-19-vaccines
20. Zanettini, C., Omar, M., Dinalankara, W., Imada, E. L., Colantuoni, E., Parmigiani, G., & Marchionni, L. (2020). Influenza vaccination and COVID-19 mortality in the USA. medRxiv. https://doi.org/10.1101/2020.06.24.20129817https://doi.org/10.1101/2020.06.24.20129817