H3N2 INFLUENZA A VIRUS

H3N2 is a subtype of the Influenza A virus, which is an important cause of human influenza. Influenza outbreaks have caused widespread illness to humans many times throughout history.

Evolution and Role of H3N2 in Pandemics

H3N2 was responsible for one of the three major influenza pandemics that occurred in the last century. In 1968, a novel strain of H3N2 influenza virus emerged in Hong Kong (A/Hong Kong/1/1968 [HK/68]) that quickly led to a pandemic that was associated with >1 million deaths world-wide. Prior to this, there was no documentation of H3N2 viruses circulating in humans. It is proposed that circulating human H2N2 viruses underwent reassortment with avian H3N2 influenza viruses which resulted in a novel H3N2 viral strain that was able to infect and transmit between humans, thereby causing the 1968 pandemic. It completely replaced the type A strain (H2N2, or Asian influenza) that had circulated throughout the world for the prior 10 years. Since their jump to humans in 1968, H3N2 viruses have rapidly evolved both genetically and antigenically in an attempt to escape host immune pressures.

A variant H3N2 virus (H3N2v) has been detected, with genes from avian, swine and human viruses and the 2009 H1N1 pandemic virus M gene. This virus was circulating in pigs in 2010 and was first detected in people in 2011. The acquisition of the 2009 M gene may make this virus infect humans more easily than is typical for other swine influenza viruses.

Circulation of H3N2

Globally there is at present, co-circulation of both H1N1 and H3N2 viruses – these are the two most predominant subtypes of Influenza A, with the majority being H1N1 viruses. So, in most countries, the non-H1N1 influenza A viruses are of the H3N2 subtype, by a wide margin (occasional cases of H5N1 are also detected). According to WHO data for 2018-19, the only countries which have H3N2 as the predominant Influenza A subtype are Belgium, France, Lithuania, Luxembourg, Turkey, and Ukraine.
Apart from the normal seasonal H3N2 virus, the H3N2v virus is circulating among swine with occasional transmission to humans (usually through direct contact with infected swine) and a total of 427 cases have been reported in the US since 2011. As of now, there is no national level surveillance or data for the H3N2v virus in India, like there is for the pandemic H1N1.

Influenza A – Real World Data

When we performed an in-house study on cases tested as part of our H1N1 profile (where samples were typed into H1N1 Influenza A and non-H1N1 Influenza A), the peak for influenza A cases (when including both H1N1 and non-H1N1 influenza) was seen to be in July and August (Figure 1).

Figure 1 – Comparison of number

Figure 1 – Comparison of number of H1N1 influenza A, non-H1N1 influenza A and influenza A negative cases, from tests done between January and November

The number and percentage of non-H1N1 positive cases peaked in July and August 2019 (figures 1 & 2).

Figure 1 – Comparison of percentages

Figure 2 – Comparison of percentages of H1N1 influenza A, non-H1N1 influenza A and influenza A negative cases from tests done between January and November

There are also a higher proportion of non-H1N1 influenza A cases from July onwards (and a corresponding dip in H1N1 cases), all the way till November (Figure 3).

Figure 3 – Trend of percentage positivity

Figure 3 – Trend of percentage positivity of H1N1 influenza A and non-H1N1 influenza A amongst the total cases tested between January and November

As mentioned earlier, almost all the non-H1N1 Influenza A viruses in circulation globally are of the H3N2 variety.

Why should we be concerned?

According to the data from the Center for Disease Control in the USA, during seasons with prominent circulation of H3N2 influenza A viruses, 2.7 times more deaths occurred than during seasons when H3N2 influenza A viruses were not prominent. Similarly, a greater number of hospitalizations occur during years that influenza A(H3N2) is predominant. Given that our real world evidence revealed that there were months in 2019 where non-H1N1 influenza A (H3N2) is the predominant subtype, this is a matter of utmost concern.

Another reason for concern is that according to a study conducted by the Haffkine institute, H3N2 strains circulating in Mumbai showed resistance to amantadine and a 16-fold reduction in oseltamivir susceptibility.

As for the H3N2v virus, it is under scrutiny by the CDC as a possible candidate for a repeat of the global 2009 Influenza outbreak. They are extremely concerned because:

  • Currently, the H3N2v has a severity similar to that of the seasonal flu. However, infections with influenza viruses (including variant viruses like H3N2v) can sometimes cause severe disease, even in healthy people. This can include complications (like pneumonia), which can require hospitalization, and sometimes result in death.
  • This virus seems to spread more easily to humans from pigs than other swine influenza viruses.
  • Influenza viruses are always changing. It’s possible the H3N2v virus could change and begin spreading easily from person to person.
  • Studies conducted by CDC and others have indicated that children born after 2001 (age ≤9 years at 2010) have little to no immunity against H3N2v viruses. Adults seem to have more immunity, perhaps because they might have been previously exposed to similar viruses in their lifetimes.

Testing algorithm for suspected influenza cases

Figure 4 – Algorithm for influenza diagnosis

Figure 4 – Algorithm for influenza diagnosis – subtyping for Influenza A is recommended

References:

  1. Allen JD, Ross TM. H3N2 influenza viruses in humans: Viral mechanisms, evolution, and evaluation. Hum Vaccines Immunother. 2018;14(8):1840–7.
  2. Pinkbook | Influenza | Epidemiology of Vaccine Preventable Diseases | CDC [Internet]. 2019 [cited 2019 Dec 26]. Available from: https://www.cdc.gov/vaccines/pubs/pinkbook/flu.html
  3. Influenza A (H3N2) Variant Virus | CDC [Internet]. 2018 [cited 2019 Dec 26]. Available from: https://www.cdc.gov/flu/swineflu/variant/h3n2v-cases.htm
  4. WHO | Recommended composition of influenza virus vaccines for use in the 2019-2020 northern hemisphere influenza season [Internet]. WHO. [cited 2019 Dec 26]. Available from: http://www.who.int/influenza/vaccines/virus/recommendations/2019_20_north/en/
  5. Novel Influenza A Virus Infections [Internet]. [cited 2019 Dec 27]. Available from: https://gis.cdc.gov/grasp/fluview/Novel_Influenza.html
  6. Gohil DJ, Kothari ST, Shinde PS, Chintakrindi AS, Meharunkar R, Warke RV, et al. Drug susceptibility of influenza A/H3N2 strains co-circulating during 2009 influenza pandemic: first report from Mumbai. Infect Genet Evol J Mol Epidemiol Evol Genet Infect Dis. 2015 Jan;29:75–81.
  7. H3N2v and You | CDC [Internet]. 2019 [cited 2019 Dec 27]. Available from: https://www.cdc.gov/flu/swineflu/variant/h3n2v-basics.htm
  8. Guidelines for laboratory procedures for detection of Influenza virus. Technical Guidelines for H1N1 :: National Centre for Disease Control (NCDC) [Internet]. [cited 2019 Dec 27]. Available from: https://ncdc.gov.in/index1.php?lang=1&level=1&sublinkid=409&lid=359
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