Can flu vaccination really reduce Covid-19 infection?

11th May 2020, Dr Chee L Khoo

flu vaccination and Covid-19

Most of you would have run out of flu vaccines by now. The bad news is that we don’t know when new stocks will arrive. So much for the assurance from the government in mid-March that “there is enough vaccines for all who needs them” but “go to your GP now anyway”. This was weeks before we could even place our order for the vaccines! Of course, we are in the middle of the Covid-19 pandemic and we are told that we don’t want to catch both the influenza virus and Covid-19 at the same time. And besides, if you catch the influenza virus, it might increase your chance of catching Covid-19 or if you do catch Covid-19, it could be more severe. Are these statements (or scare tactics) actually true?

Let’s look at a few questions we are seeking answers for:

Do co-infections exist?

It has long been known that simultaneous viral infections exhibit a phenomenon called viral interference where one virus blocks the growth of another virus (1-4), so the concept of simultaneous respiratory infections in patients is somewhat surprising.

Children are the most common victims of simultaneous virus infections. An investigation by Goka et al. (5) reported that children aged less than 5 years show a higher propensity for viral co-infection than others. So, co-infections do exist and not that uncommon especially in children.

Are co-infections worse or better than single infections?

The severity of viral co-infections on clinical outcome in these patients, however, is still unclear. Some investigations concluded that viral co-infections are no more severe than single virus infections (6-8), or even that there is less severe clinical impact associated with co-infection (6,9) while other studies have evidence of severe disease outcome from viral co-infections (10,11).

Aberle et al. (12) found that the severity of dual infections with non-RSV respiratory viruses are similar to those of single infections, whereas co-infection with respiratory syncitial virus (RSV) is associated with reduced immune responses resulting in a more severe clinical course of lower respiratory tract diseases. Brand et al. (13) also found that RSV associated co-infections are more severe than single RSV infections. Co-infections with influenza A and B viruses also appear to increase severity, leading to higher rates of admission to intensive care units or death (5). Why the contradiction? It would appear that the outcome of co-infection depends on which is the primary infection.

In a brilliant experiment, Shinjoh et al showed that the growth of RSV is blocked by competitive infection with influenza A virus (14). Influenza A virus has the potential to block the growth of RSV if they infect the host cells at the same time. If RSV infect the host first, RSV can suppress influenza viral multiplication. It is thought that the viruses compete for the resource of target cells, so that viruses with a higher growth rate will out-compete viruses with a lower growth rate since the faster growing virus will consume more target cells early in the infection.

From a practical point of view, if we treat the influenza when a patient have both RSV and influenza infection, the RSV might get worse since the influenza virus stop suppressing RSV multiplication.

So, do patients with Covid-19 and influenza fare worse? We don’t know.

Does the presence of influenza infection increase your chance of Covid-19 infection?

In a recent report from the Clinic University Hospital of Valencia, Spain, 183 patients who tested positive for SARS-CoV 2 using RT-PCR swabs and who were hospitalised for pneumonia , between March 4 and 28th 2020 were tested for other RP (Adenovirus, Influenza A, Influenza A (H1), Influenza A (H3), Influenza B, Parainfluenza virus 1-4, non-Covid-19 coronavirus, Respiratory Syncytial Virus A & B, Metapneumovirus, Human Bocavirus, Rhinovirus-Enterovirus, Chlamydophila pneumoniae and Mycoplasma pneumoniae) (15).

Amongst the non-covid-19 RP, co-infections were quite common (25%) which were rather comparable to previous years (~35%). However, in patients who were positive for Covid-19 (n=102), only 2 also tested positive of other RP. Interestingly, in patients with symptoms and radiological features which were suspicious of Covid-19 but tested negative, 6 out of 23 (24%) tested positive for other RP.

Are our so-called respiratory clinics looking for other causes of the flu symptoms apart from testing for Covid-19? Are they just “swabbing clinics”? Telehealth without face to face consultations may miss many other respiratory infections that are treatable.

Do flu vaccinations reduce Covid-19 infections or reduce the severity of Covid-19 if we get it?

SARS-CoV-2 seem to less commonly infect children and to cause milder symptoms and are associated with much lower case-fatality rates and most of them recover quickly from the infection. One possible explanation is that these immunisations may build the immunity against SARS-CoV-2 protecting lung cells from invasion. Most routine viral vaccines are either inactivated or killed vaccines stimulate T Helper 1 cells (CD4+) to secrete many different types of cytokines as interferon gamma, interleukin-2 and IL-12. IL-2 provokes the maturation of the killer T cell and improve the cytotoxicity of natural killer cells recognising and destroying cells infected with viruses (16).

Besides the cross-reactivity effect, the anti-Flu immune responses can induce bystander immunity that is expected to non-specifically augment immunity against other viral infection such as SARS-CoV-2 (17) .

Thus, we don’t have data yet but could that vaccination against influenza prime our immune response if we meet the SARS-CoV 2 virus and reduce our susceptibility to Covid-19? We don’t know the answer to that question yet.

So, should we recommend flu vaccinations for all because of the Covid-19 pandemic? Well, not for the reasons often cited (“to reduce the risk of a dangerous double-up of seasonal influenza and Covid-19”) as the evidence for the recommendation is really thin.

However, by reducing the complications of influenza, we could reduce hospital bed use for complications from influenza infection during the Covid-19 pandemic. Flu vaccinations have been shown to reduce hospitalisations from complications of influenza. Now, that is a reason I can accept.

References:

  1. Henle W. Interference Phenomena Between Animal Viruses: A Review. J Immunol. 1950; 64:203–236. PMID: 15412251
  2. Findlay GM, MacCallum FO. An interference phenomenon in relation to yellow fever and other viruses. J Path Bact. 1937; 44(2):405–424. doi: 10.1002/path.1700440216
  3. Andrewes CH. Interference by one virus with the growth of another in tissue-culture. Brit J Exp Path. 1942; 23(4):214–220.
  4. Ziegler JE, Horsfall F. Interference between the influenza viruses: 1. The effect of active viruses upon the multiplication of influenza viruses in the chick embryo. J Virol. 2002 May; 76(9):4420–4429.
  5. Goka EA, Vallely PJ, Mutton KJ, Klapper PE. Single, dual and multiple respiratory virus infections and risk of hospitalization and mortality. Epidemiol Infect. 2015 January; 143(1):37–47. doi: 10.1017/S0950268814000302 PMID: 24568719
  6. Martin ET, Fairchok MP, Stednick ZJ, Kuypers J, Englund JA. Epidemiology of Multiple Respiratory Viruses in Childcare Attendees. JID. 2013 January; 207:982–989. doi: 10.1093/infdis/jis934 PMID:23288925
  7. Brand HK, de Groot R, Galama JMD, Brouwer ML, Teuwen K, Hermans PWM, et al. Infection With Multiple Viruses is not Associated With Increased Disease Severity in Children With Bronchiolitis. Pediatr Pulmonol. 2012 April; 47(4):393–400. doi: 10.1002/ppul.21552 PMID: 21901859
  8. Rotzen-Ostlund M, Eriksson M, Lindell AT, Allander T, Wirgart BZ, Grillner L. Children with multiple viral respiratory infections are older than those with single viruses. Acta paediatr. 2014 January; 103 (1):100–104. doi: 10.1111/apa.12440 PMID: 24117958
  9. Martin ET, Kuypers J, Wald A, Englund JA. Multiple versus single virus respiratory infections: viral load and clinical disease severity in hospitalized children. Influenza and other respir viruses. 2011 May; 6 (1):71–77. doi: 10.1111/j.1750-2659.2011.00265.x
  10. Global Burden of Disease Study. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015 August 22; 386(9995):743–800. doi: 10.1016/S0140-6736(15)60692-4 PMID: 26063472
  11. Waner JL. Mixed viral infections: detection and management. Clin Microbiol Rev. 1994 April; 7(2):143–151. PMID: 8055464
  12. Aberle JH, Aberle SW, Pracher E, Hutter HP, Kundi M, Popow-Kraupp T. Single Versus Dual Respiratory Virus Infections in Hospitalized Infants Impact on Clinical Course of Disease and Interferon γ Response. Pediatr Infect Dis J. 2005 July; 24(7):605–610. doi: 10.1097/01.inf.0000168741.59747.2d PMID: 15999001
  13. Brand HK, de Groot R, Galama JMD, Brouwer ML, Teuwen K, Hermans PWM, et al. Infection With Multiple Viruses is not Associated With Increased Disease Severity in Children With Bronchiolitis. Pediatr Pulmonol. 2012 April; 47(4):393–400. doi: 10.1002/ppul.21552 PMID: 21901859
  14. Shinjoh M, Omoe K, Saito N, Matsuo N, Nerome K. In vitro growth profiles of respiratory syncytial virus in the presence of influenza virus. Acta Virologica. 2000; 44(2):91–97. PMID: 10989700
  15. Blasco ML, Buesa J, Colomina J, et al. Co-detection of respiratory pathogens in patients hospitalized with Coronavirus viral disease-2019 pneumonia. J Med Virol. 2020;
  16. P.V. Baskar, G.D. Collins, B.A. Dorsey-Cooper, R.S. Pyle, J.E. Nagel, D. Dwyer, et al.Serum antibodies to HIV-1 are produced post-measles virus infection: evidence for cross-reactivity with HLA Clin Exp Immunol [Internet], 111 (2) (1998 Feb), pp. 251-256
  17. F. Horns, L.C. Dekker, S.R. QuakeMemory B cell activation, broad anti-influenza antibodies, and bystander activation revealed by single-cell transcriptomics Cell Rep, 30 (2020), pp. 905-913