A new pandemic

Adjusted for population, it would equal 150K lives lost today; more than lost during the 1957 H2N2 pandemic.

Admittedly, bacterial pneumonia likely contributed to these numbers, but it shows the extreme impact a non-pandemic flu season can have.  

In the opening years of WWII, the US military – fearing that crowded ships and barracks could spark a reprise of the 1918 pandemic – commissioned Dr. Thomas Francis of the University of Michigan and his protégé Jonas Salk to come up with a viable influenza vaccine.   

Within a year a vaccine based on the 1934 and 1943 flu strains was in wide use in the military, and for several years the Francis/Salk vaccine worked well. 

But in 1947, a new variant of the H1N1 virus appeared on military bases – first reported in Japan – and quickly spread from there infecting hundreds of millions around the globe (see 2002 PNAS article). 

While it produced a generally mild illness, and few excess deaths, this new strain had drifted enough antigenically to evade both the vaccine and community immunity acquired from earlier strains. 

1947 is little remembered today, except for the lesson it taught us; that vaccines must be updated nearly each year to take into account antigenic drift (or newly emerging flu strains).

Four years later, a far more ominous viral strain made a brief appearance on the global stage, during what was an otherwise mild and unremarkable 1950-51 flu season.  

This outbreak is often called the Liverpool Flu, and for about six weeks, it caused a virulent flu virus to spread across the UK and into Canada – that for a time - was as deadly as the 1918 pandemic.

In 2006 the CDC's EID Journal published a stellar account of this event, and it is very much worth reading. 

Viboud C, Tam T, Fleming D, Miller MA, Simonsen L. 1951 influenza epidemic, England and Wales, Canada, and the United States. Emerg Infect Dis [serial on the Internet]. 2006 Apr [date cited].

While presumably a variant of the seasonal A/H1N1 strain, we still don't know what made that virus so deadly, or why it failed to return the following year. 

A pandemic strain (H2N2) did emerge in 1957 - following an avian/seasonal flu reassortment event - that produced several delayed waves in 1960 and 1963 in the United States and a sharp resurgence in the UK in 1967.

Eleven years later (1968), an avian H3 virus reassorted with H2N2 in Asia, and generated a pandemic H3N2 virus which would dominate until 1977.  

In February of 1976, however, a young recruit at Ft. Dix, New Jersey fell ill and died within 24 hours. The virus went on to infect more than 200 soldiers and caused severe respiratory disease in 13 of them. It circulated on the base for nearly a month.

 The virus was isolated and dubbed A/New Jersey/76 (Hsw1N1). How it arrived on the base was unknown. While the death rate was very low, this virus appeared to easily transmissible among humans. 

And the fear was, it might develop a higher mortality rate as it mutated. 

This led to the swine flu pandemic scare of 1976, which I've chronicled several times over the years (see Deja Flu, All Over Again). The feared swine flu pandemic never materialized, and for reasons we cannot explain, the virus simply disappeared.

But a year later, we did see an epidemic, at least among children, with the return of the H1N1 virus after a 20 year absence. Evidence suggests this may have come about due to a lab leak in Russia or China, which were suspected of conducting vaccine research for the 1976 `swine flu'

Microorganisms: The Growing Phenomenon of ‘Frozen’ Virus Genome Sequences and Their Likely Origin in Research Facility Escapes

It isn't always a new virus, however.  Sometimes old flu viruses learn new tricks.

Two decades ago Amantadine was the preferred influenza antiviral. It was cheap, plentiful, and worked reasonably well as both a treatment, and a preventative. But its overuse - reportedly even in chicken feed in China- led to widespread resistance, and by 2006 the CDC no longer recommended its use.

Tamiflu (oseltamivir) - an NAI (neuraminidase inhibitor) - became the new treatment standard. While occasional instances of Oseltamivir resistance were recorded prior to 2007, in nearly every case, it developed after a person was placed on the drug (i.e. `spontaneous mutations’).

Studies suggested that these resistant strains were `less biologically fit’, and were therefore unlikely to spread from human-to-human.

That is, until `biologically fit' resistant H1N1 viruses emerged and began circulating in early 2008. By the end of the year - nearly all H1N1 viruses were resistant, forcing the CDC to issue major new guidance for the use of antivirals (see CIDRAP article With H1N1 resistance, CDC changes advice on flu drugs).

An antiviral crisis was averted when in 2009 a new swine-origin H1N1 virus -  one that happened retain its sensitivity to Tamiflu - swooped in as a pandemic strain, supplanting the older resistant H1N1 virus. 

While this 2009 H1N1 virus was considered relatively mild, in a small percentage (1%-2%) of patients a mutation (D225G) was known to produce more serious, deep-lung, infections. 

This mutation remains rare, but we've seen several clusters emerge (see here, here, and here) over the past dozen years, which keeps it on our watch list.

This famed unpredictability of influenza has provided a number of problematic flu seasons over the past decade, including: 

• In 2014, we saw a late summer mutation appear in the H3N2 virus (see HAN Advisory On `Drifted’ H3N2 Seasonal Flu Virus) which greatly reduced the effectiveness of that year's flu vaccine.

• In 2016, we saw new warnings over mutated (D225G) H1N1 viruses in Russia and in Europe (see ECDC Risk Assessment : Reports Of Severe A(H1N1)pdm09 In Europe).

• In 2017 the H3N2 sparked a particularly rough flu season (see MMWR: Reviewing Our High Severity 2017-2018 Flu Season), which was poorly controlled by an under-performing vaccine. 

• And since last year we've been monitoring some sporadic, but worrisome signs of creeping antiviral resistance (see Eurosurveillance: An outbreak of A(H1N1)pdm09 Exhibiting Cross-resistance to Oseltamivir & Peramivir in an Elementary School in Japan, Sept 2024).

We tend to trivialize seasonal flu, forgetting that it is capable of reassorting with other (avian/swine) flu viruses to produce pandemics, that it can abruptly increase in virulence on its own, and it continually evolves to evade vaccines and/or antivirals.  

Our complacency has translated into a significant drop in seasonal flu vaccine uptake over the past 5 years, and far too many people go to work, or to school, while still contagious.   

While a novel flu virus would likely be worse, they generally emerge only a few times each century.  Seasonal flu comes around every year, and history has repeatedly shown that these viruses should not be underestimated.