Virus evolution: from

SARS-CoV-2 to avian influenza

Jesse Bloom

Fred Hutch Cancer Center / HHMI

These slides at https://slides.com/jbloom/virus-evol-general

Panum (1847)

The Faroe Islands

"Measles had not prevailed on the Faroes since 1781, then it broke out early in April 1846."

Panum (1847)

"Of the 7782 inhabitants, about 6000 were taken with measles."

Panum (1847)

Panum (1847)

Panum was describing immune memory, which provides lifelong protection from measles

By 1970, vaccines had been developed that conferred effective immunity to measles as well as many other viruses

"[T]he most likely forecast about the future of infectious disease is that it will be very dull."

- Nobel laureate Mcfarlene Burnet (1972)

Unfortunately, viral evolution has kept infectious diseases from becoming boring...

Inherent transmissibility versus effective transmissibility given population immunity

R0 (inherent transmissibility): average number of infected contacts of each case in absence of population immunity. Measles has highest R0 (12 to 18) of any human respiratory virus.

Inherent transmissibility versus effective transmissibility given population immunity

R0 (inherent transmissibility): average number of infected contacts of each case in absence of population immunity. Measles has highest R0 (12 to 18) of any human respiratory virus.

Inherent transmissibility versus effective transmissibility given population immunity

R0 (inherent transmissibility): average number of infected contacts of each case in absence of population immunity. Measles has highest R0 (12 to 18) of any human respiratory virus.

Rt (effective transmissibility): average number of infected contacts given actual population immunity. Because immunity to measles is potent and durable, vaccination can drive measles virus Rt to below one (ie, herd immunity).

Inherent transmissibility versus effective transmissibility given population immunity

R0 (inherent transmissibility): average number of infected contacts of each case in absence of population immunity. Measles has highest R0 (12 to 18) of any human respiratory virus.

Rt (effective transmissibility): average number of infected contacts given actual population immunity. Because immunity to measles is potent and durable, vaccination can drive measles virus Rt to below one (ie, herd immunity).

But if a virus evolves rapidly to erode immunity, it is not possible to achieve herd immunity

Original COVID-19 vaccine induced high neutralizing antibody titers to early strains

Lasrado et al (2023)

But later SARS-CoV-2 variants contained mutations that eroded antibody immunity

Lasrado et al (2023)

newer viral variants

Evolutionary tree

H5N1 influenza: will virus evolve inherent transmissibility to cause human pandemic?

There is very little neutralizing antibody immunity to H5N1 influenza in humans, so virus will cause pandemic if it becomes sufficiently transmissible (R0 > 1)

However, so far the virus is not transmissible among humans (nearly all human cases are direct animal infections)

We worry because animal influenza strains have caused human pandemics before

Influenza pandemics have occurred for at least 500 years (Morens et al, 2010). Most recently:

  1918: animal virus (maybe from birds?) jumped to humans (dos Reis, 2009)

  1957: avian virus reassorted HA / NA / PB1 with human strain (Palese, 2004)

  1968: avian virus reassorted HA / PB1 with human strain (Palese, 2004)

  1977: inadvertant human release of strain from ~1950s (Burke & Schleunes, 2024)

  2009: swine virus jumped to humans (Smith et al, 2009)

But there are also many animal strains that never adapted to humans

In 1872, influenza caused major outbreaks in poultry and horses, but likely never spread in humans beyond sporadic cases (Morens & Taubenberger, 2010)

There are multiple influenza strains in pigs that so far have only caused sporadic human cases (Anderson et al, 2021)

Influenza has caused substantial outbreaks in dogs without infecting humans (Parrish, 2015)

Molecular properties thought to promote human transmissibility

Viral polymerase functions well in mammalian cells (Long et al, 2019)

Binds human receptors (Matrosovich, 2000; Ayora-Talavera, 2009)

Higher hemagglutinin stability (Imai, 2012; Herfst, 2012)

Nucleoprotein resistant to MxA and BTN3A3 (Manz et al, 2013, Pinto 2023)

Appropriate hemagglutinin-neuraminidase balance (Yen, 2011)

Probably other adaptations that are not well understood

Viral polymerase functions well in mammalian cells (Halwe et al, 2024)

Binds human receptors (Santos et al, 2024; Chopra et al, 2024)

Higher hemagglutinin stability (Peacock et al, 2024)

Nucleoprotein resistant to MxA and BTN3A3 (Ankerhold et al, 2025)

Appropriate hemagglutinin-neuraminidase balance

Probably other adaptations that are not well understood

Are there currently signs of H5N1 gaining human-transmissibility adaptations?

Yes

No

(at least so far)

Unknown

(at least in public literature to date)

"It's tough to make predictions, especially about the future."

- Yogi Berra

If there is a H5N1 pandemic, vaccines will be most important countermeasure

But as influenza evolves, candidate vaccines can become poorly matched to the actual viruses of concern. (This is why it doesn't make sense to stockpile hundreds of millions of doses of H5N1 vaccines like we've done for smallpox.)

So we need to monitor H5N1 antigenic evolution to prepare candidate vaccines to scale up rapidly if needed.

A goal of my lab's research is to enable informed interpretation of viral mutations

Dadonaite et al, 2024

H5N1 influenza is a biosafety-level-3 potential pandemic pathogen. Therefore, we use safe pseudovirus systems to study mutants of viral proteins.

Actual virus:

human pathogen

Pseudovirus:

cannot replicate on its own

Takeaways

For some viruses (eg, measles) immunity can provide lifelong protection and vaccines can create population-level herd immunity.

Other viruses (eg, SARS-CoV-2) evolve rapidly to escape immunity making herd immunity is impossible (vaccines can still reduce transmission and mitigate disease).

If a novel virus (eg, H5N1 influenza) acquires sufficient transmissibility, it will cause pandemic because there is no immunity.

Pandemics are inherently difficult to predict, but research can help with monitoring/interpreting viral evolution and informing vaccine development.