Sunday, July 05, 2020

The CDC's Responds to the PNAS EA H1N1 `G4' Swine Flu Study


Six days ago, in PNAS: Eurasian Avian-like H1N1 Swine Influenza Virus With Pandemic Potential In China, we took a look at a recent study - and more than 5 years of previous research - on an emerging swine flu virus spreading in pigs in Mainland China. 

While touted as a `new threat' by many media outlets, this virus has been around and on our radar  for years, and has been cited as having substantial `pandemic potential' since at least 2015 (see PNAS: The Pandemic Potential Of Eurasian Avian-like H1N1 (EAH1N1) Swine Influenza).

While EA H1N1 is considered a top contender for sparking a future pandemic, it is far from the only swine flu virus we are watching.  The CDC's IRAT (Influenza Risk Assessment Tool) lists 3 North American swine viruses as having pandemic potential (2 added in 2019).

H1N2 variant [A/California/62/2018]  Jul   2019  5.8  5.7 Moderate
H3N2 variant [A/Ohio/13/2017]          Jul   2019  6.6  5.8 Moderate
H3N2 variant [A/Indiana/08/2011]      Dec 2012   6.0  4.5 Moderate

We've also been closely watching a number of other swine influenza reassortants around the world, including:

EID Journal: Human-Origin Influenza A(H3N2) Reassortant Viruses in Swine, Southeast Mexico

JVI: Divergent Human Origin influenza Viruses Detected In Australian Swine Populations

Globally, surveillance for swine flu viruses - both in pigs, and occasionally jumping to other species (including humans) - is weak, but the evidence suggests human infection probably happens with far more frequency than we hear about. 

study published in 2013 (see CID Journal: Estimates Of Human Infection From H3N2v (Jul 2011-Apr 2012)- estimated that during a time when only 13 cases were reported by the CDC - that the actual number of infections was likely 200 times (or more) higher.
Results. We estimate that the median multiplier for children was 200 (90% range, 115–369) and for adults was 255 (90% range, 152–479) and that 2055 (90% range, 1187–3800) illnesses from H3N2v virus infections may have occurred from August 2011 to April 2012, suggesting that the new virus was more widespread than previously thought.
So far, we've not seen a swine flu virus really take off in the human population since the 2009 pandemic, but the potential for that happening again is obviously there.

And as we've discussed many times before (see Are Influenza Pandemic Viruses Members Of An Exclusive Club?) - most swine influenza viruses are either H1, H2, or H3 - giving them a distinct advantage, as those are the only influenza subtypes known to have sparked a human pandemic in the last 130 years. 

The good news is that most novel viruses - even those that are capable of occasionally jumping to humans - simply aren't biologically `fit' enough to spark a pandemic.  In order to be successful, they need to be able to replicate and transmit on par with already circulating human flu viruses. 

Our ability to predict the `next pandemic' virus has a perfect record.  It has never happened.  Every pandemic - including the current one - came out of left field, while we had our eyes elsewhere.
Someday maybe we'll get there, but for now our best bet is to identify potential threats as they emerge  (see CDC Adds 3 Novel Flu Viruses To IRAT List), track and study them as best we can, develop and continually update a roster of Candidate Vaccine Viruses (CVV), and do a much better job in general pandemic preparedness. 
Whether the next pandemic will stem from EA H1N1 is anyone's guess.  But another pandemic is inevitable, and EA H1N1 `G4' appears to have many of the traits we look for in a novel virus.

Late last week the CDC published the following response to the PNAS `G4' study. 

July 2, 2020 – A recent publication in the journal Proceedings of the National Academy of Science (PNAS)external icon describes a group of H1N1 swine influenza viruses that have “the essential hallmarks of being highly adapted to infect humans” and which are therefore of potential pandemic concern.

This group of viruses, referred to as “G4” Eurasian (EA) avian-like H1N1 viruses, has been spreading in pigs in China since 2016 and has become the predominant genotype found in Chinese pigs. According to the report, these viruses have the right characteristics for causing infections in people, including the ability to grow well in human lung cells and to spread by respiratory droplets and direct contact in an animal model. While only two human infections with G4 viruses have previously been reported, this study found that about 10% of swine workers from whom blood samples were taken in China had evidence of prior infection with G4 viruses, suggesting that human infection is more common than previously thought.
It’s important to note that there are no reports of G4 viruses spreading from person-to-person, a characteristic that is required in order for a pandemic to occur. Also, G4 viruses have not been detected in pigs or people in the United States. However, like all flu viruses with pandemic potential, CDC is taking a number of actions to monitor and prepare against this emerging public health threat, including:
  • Coordinating with public health partners in China, including requesting a virus sample
  • Assessing the risk of the virus causing a pandemic using CDC’s Influenza Risk Assessment Tool (IRAT)
  • Evaluating whether an existing candidate vaccine virus (CVV) against a closely related flu virus (called “G5”) would protect against this virus,
  • If needed, creating a new CVV specific to G4 viruses, and
  • Studying whether existing flu antiviral drugs offer protection against this group of viruses.
G4 swine flu viruses in China described in the PNAS report have a mix of genes from influenza viruses found in humans, birds and pigs. Five genes of the G4 virus came from the 2009 H1N1 virus that caused the 2009 flu pandemic. Based on laboratory transmission studies in ferrets, G4 viruses can spread via direct contact or via respiratory droplets. CDC has tested a closely related G5 virus in its laboratories and observed transmission similar to what was reported in this study.

G4 viruses likely resulted from a process called “reassortment,” which occurs when two or more influenza viruses infect a single host and exchange genetic material. This can sometimes lead to the emergence of new influenza viruses in people or animals. Pigs have been identified as a sort of “mixing vessel” for reassortment to occur because pigs are susceptible to infection with influenza viruses found in pigs, birds and humans. The 2009 H1N1 pandemic arose from a reassortment event between pigs, birds and human influenza A viruses.

The PNAS study showed that among 338 swine works whose blood was tested for antibodies, about 10% had evidence of past infection with G4 viruses. A higher rate was observed among 18-35-year-old swine workers. Regular households also were sampled, and about 4% of the 230 people from the general population had antibodies to G4 viruses. These data suggest that these viruses may have acquired increased capability of infecting humans. Study authors caution that continued circulation of these viruses in pigs and exposure to humans may allow for additional reassortment events to occur and that these viruses and infections should be monitored closely.

Experts believe most people would lack immunity against G4 viruses, and despite seasonal flu vaccines protecting against the 2009 H1N1 virus, G4 viruses are different enough that seasonal flu vaccines would be unlikely to provide protection or prevent onward human-to-human transmission.

A prototype candidate vaccine virus (CVV) from the closely related EA avian-like H1N1 G5 swine flu virus was originaly developed by the World Health Organization (WHO) Collaborating Center at the China CDC. A comparison of the genome of this virus to that of G4 viruses reveals that these two viruses are similar. Studies are planned to assess cross-reactivity between this vaccine virus and G4 viruses. If needed, CDC will work to create a new CVV made specifically against G4 viruses.

CDC and its public health partners around the world will continue to monitor this situation closely.