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Influenza A subtypes are categorized by two proteins they carry on their surface; their HA (hemagglutinin) and NA (neuraminidase). There are 17 known HA proteins, and 10 known NAs, making many different subtype combinations possible, although only a few are known to infect humans.
While we talk about H1N1 or H3N2 seasonal flu as if each were a single entity, in truth, there can be much variation within each subtype. Within each subtype, there are often genetic groupings called clades, and within each clade- subclades - and within these even smaller genetic variations.
The ECDC’s most recent Influenza Virus Characterisation Report (Sept. 2013) found that the 2009 H1N1 virus HA genes have morphed into eight different genetic groups (clades), with a ninth ‘outlier’ group largely restricted to countries of west Africa. Similarly, the H3N2 viruses circulating over the past year fall into 3 groups (3, 5, 6), with three subgroups (3A, 3B, 3C) and subgroup 3C has 3 subsets (3C.1, 3C.2, 3C.3).
This expanding variety in each strain is due to antigenic drift, which comes about when errors are made in the replication of the virus. Over a period of a few hours, millions of copies of a virus can be produced in a single host, and invariably some of these copies are `flawed’, and contain amino acid substitutions somewhere in the virus’s genetic code.
Most of the time, these changes either do nothing, or make the virus less viable. With millions of copies being generated, a few `duds’ hardly makes a difference to the virus, or the host.
But every once in awhile, out of millions of failures, a more biologically `fit’ virus will emerge. One that replicates better than either its parents or its siblings - and if it is also easily transmissible - it can take off as a new, emerging variant or (if it is genetically distinct enough) as a new clade.
These new clades can change the virus antigenically (evading existing immunity), can convey resistance to antivirals, and can even change the virulence of the virus.
This is why the flu vaccine must be updated nearly every year. Flu viruses mutate constantly, and over time new clades (and sometimes, entirely new strains) appear. Even more abrupt changes can come from Antigenic Shift or reassortment (see Because, Sometimes Shift Happens).
And, as you might expect, the same is true with avian and swine influenza viruses.
Since the H5N1 virus was first identified in 1996 it has expanded into more than 20 different clades and subclades, and various versions of the virus now circulate in different parts of the world. You can see the evolution of the virus through 2011 in the chart below.
NOTE: Not all of these clades continue to circulate.
Clade 2.3.2 (and now 2.3.2.1) are very common in South East Asia, clades 2.2.1 and 2.2 are endemic in Egypt and clades 2.1.1, 2.1.2. and 2.1.3 are found in Indonesia.
As you might imagine, as new clades emerge, it complicates the vaccine picture enormously, for humans and for poultry. A vaccine designed for clade 1.0 probably won’t prove very effective against clade 2.2.
Last month (see WER: Antigenic & Genetic Comparisons Of Zoonotic Flu Viruses And Development Of Vaccine Candidates) the WHO proposed that 4 new candidate vaccine viruses be developed.
Based on the available antigenic, genetic and epidemiologic data, A/duck/Bangladesh/19097/2013-like (clade 2.3.2.1), A/duck/Viet Nam/NCVD-1584/2012-like (clade 2.3.2.1) and A/Cambodia/W0526301/2012-like (clade 1.1) candidate vaccine viruses are proposed.
Not all H5N1 viruses possess the same virulence, and some strains may be more readily transmissible than others. Last April we looked at a study that examined the Differences In Virulence Between Closely Related H5N1 Strains.
All of which serves as prelude to a new Dispatch that appeared this week in the CDC’s EID Journal, that reports the emergence of three new variations of the H5N1 virus in Vietnam between 2009 and 2012.
Novel Variants of Clade 2.3.4 Highly Pathogenic Avian Influenza A(H5N1) Viruses, China
Min Gu, Guo Zhao, Kunkun Zhao, Lei Zhong, Junqing Huang, Hongquan Wan, Xiaoquan Wang, Wenbo Liu, Huimou Liu, Daxin Peng, and Xiufan Liu
Abstract
We characterized 7 highly pathogenic avian influenza A(H5N1) viruses isolated from poultry in China during 2009–2012 and found that they belong to clade 2.3.4 but do not fit within the 3 defined subclades. Antigenic drift in subtype H5N1 variants may reduce the efficacy of vaccines designed to control these viruses in poultry.
<SNIP>
Conclusions
The location of the 7 HPAI A(H5N1) virus variants in the HA gene tree (Figure) suggests that novel monophyletic subclades other than the previously identified 2.3.4.1, 2.3.4.2, and 2.3.4.3 subclades continue to emerge within clade 2.3.4. As a result of our findings, we suggest that these groups should be assigned new fourth-order clades of 2.3.4.4, 2.3.4.5, and 2.3.4.6 to reflect the wide divergence of clade 2.3.4 viruses.
In China, 1 of the 6 countries to which subtype H5N1 virus is endemic (7), multiple distinct clades (2.2, 2.5, 2.3.1, 2.3.2, 2.3.3, 2.3.4, 7, 8, and 9) were identified by surveillance during 2004–2009 (5). In particular, clades 2.3.2, 2.3.4, and 7 viruses have gained ecologic niches and have continued circulating by further evolving into new subclades (2). In addition, various NA subtypes of H5 viruses (H5N5, H5N8, and H5N2) bearing the genetic backbone of clade 2.3.4 A(H5N1) viruses have been detected in ducks, geese, quail, and chickens (8–12). These findings highlight the importance of periodic updates of the WHO/OIE/FAO classification of Asian A(H5N1) viruses by continuous surveillance to better understand the dynamic nature of the viral evolution.
Our findings have implications for the effectiveness of vaccination of chickens against HPAI A(H5N1) viruses. The results of cross-HI assays (Table 1) and vaccine efficacy experiments (Table 2) indicate antigenic drift in subtype H5N1 variants, as compared with the vaccine strain specifically designed to control the prevalent clade 2.3.4 virus infection in poultry. Although previous studies by Tian et al. (13) and Kumar et al. (14) proposed that vaccinated chickens with HI antibody titers of >4 log2 could be protected from virus challenge, our data demonstrate that vaccine efficacy is substantially influenced by antigenic matching between the vaccine strain and circulating viruses in preventing the replication and transmission of influenza virus, especially when the induced antibodies are of moderate titers.
While we’ve been fortunate that no human-transmissible strain of H5N1 has evolved over the years, there are no guarantees that an emerging variant won’t gain that ability down the road.
And, assuming the H7N9 virus doesn’t fade away on its own accord, there is little reason not to expect a similar evolutionary expansion as more hosts are infected and more copies of itself are generated, which will provide more opportunities for new successful variants to be created.
The only thing you can truly bank on with influenza viruses is that they continually change. And until an effective universal vaccination can be developed against them, they will continue to pose a considerable threat to humanity.
