Overview

The H3N2v virus, a variant of the H3N2 influenza strain, has become a significant concern in public health due to its rapid evolution and impact on human populations. Over the years, the virus has continuously adapted, making it challenging to predict and control, leading to seasonal epidemics with varying severity. This article explores the evolving nature of H3N2v, its transmission pathways, symptoms, and broader public health implications, highlighting the ongoing challenges in combating this ever-changing virus. 

What is the H3N2 virus?

Influenza is a respiratory illness that primarily affects the lungs and airways, causing symptoms such as fever, cough, and body aches. Each year, influenza impacts approximately 5–15% of the global population.¹ There are two main types of influenza viruses: influenza A and influenza B. This article will focus on H3N2, a subtype of the influenza A virus, and its impact on human health.¹

Why is the evolution of H3N2 important?

The H3N2 influenza virus was first introduced into the human population in 1968, causing a global pandemic that resulted in approximately 1 million deaths worldwide. Since then, the virus has undergone significant changes, both genetically and antigenically. Genetically, H3N2 has mutated, altering its genetic code, while antigenically, the surface proteins (hemagglutinin (H3) and neuraminidase (N2)) have evolved, changing their 3D shape. These alterations allow the virus to evade immune detection, making it more challenging for the body’s immune system to recognize and fight the virus, which underscores the importance of monitoring and adapting vaccines to keep pace with these changes.¹

Your immune system identifies viruses by the unique shape of antigens on their surface. When these antigens change shape, such as by adding new molecules, it becomes more difficult for your immune system to recognise and attack the virus if it reinfects you. As a result, your body must produce new antibodies to combat the altered virus. The evolution of H3N2 makes it increasingly challenging for vaccines to effectively target and prevent infection, highlighting the need for regular updates to the vaccine to address the constantly changing virus.¹

Evolutionary history of the H3N2 virus

Origin and emergence

In the early 1960s, several viruses responsible for respiratory diseases in turkeys, ducks, and quails were isolated.¹ Specifically, in 1961, an outbreak of influenza A in wild birds in South Africa suggested that wild birds might be a reservoir for influenza A viruses. By 1967, a connection between human and avian (bird) influenza A viruses was proposed, as the same influenza A strain responsible for the 1957 human pandemic was also found in turkeys. This raised questions about whether influenza viruses originate from humans or birds. While the exact origin of H3N2 remains uncertain, it has been concluded that its genes are derived from a mix of avian, swine, and human sources.¹

Which genes does the H3N2 virus contain and where did they originate from?

The 1968 H3N2 influenza pandemic was caused by a virus with a unique genetic composition:

• Two genes from avian influenza viruses
• A new subtype of hemagglutinin (H3), a surface protein that enables the virus to bind to host cells
• The neuraminidase protein (N2) from the H2N2 influenza A virus, which caused the 1957 pandemic

The H3N2 virus is a genetic mix of avian, swine, and human influenza genes, and these surface proteins play a crucial role in how the virus infects host cells. The figure below provides an explanation of the origins of these proteins.

Figure 1 Influenza H3N2. Created by Alisha Solanki, created using BioRender.

Genetic mutations and variations

The genes for hemagglutinin and neuraminidase can undergo mutations, causing changes in the proteins due to substitutions in the amino acids, which are the building blocks of proteins. These substitutions alter how the proteins are structured and folded, leading to changes in their 3D shape. As a result, new variations of the H3N2 virus can emerge, making it harder for your immune system to recognize and fight the new strain. This process, known as antigenic drift, played a key role in the 2012 H3N2 influenza endemic in Southern China.^2,3

Transmission dynamics

H3N2 can spread from human to human through tiny droplets released when an infected person speaks, coughs, or sneezes. These droplets can be inhaled by others, potentially leading to infection. Additionally, the virus's transmission dynamics are influenced by genetic variations that occur through processes like antigenic drift.^2,3  

Vaccination can reduce the risk of infection in the general population, with effectiveness ranging from 40-60% when the vaccine is well-matched to the circulating strain.

The duration of virus shedding also plays a role in transmission. This refers to how long an individual remains contagious, even after symptoms have resolved. However, the exact duration of viral shedding for H3N2 is still unknown, making it difficult to fully understand its impact on transmission dynamics.

Impact on human health

Symptoms and severity

The symptoms of an H3N2 infection can range from mild to severe and vary between individuals. You may experience some or all of the following:⁴

• Fever or chills
• Headache
• Cough
• Sore throat
• Body or muscle aches
• Runny nose or nasal discharge
• Vomiting
• Diarrhea

Vulnerable populations

According to the World Health Organization (WHO), those who are more vulnerable to the H3N2 virus are:

• Healthcare workers who may come into more frequent contact with the virus
• Pregnant women
• Those who are aged 65 and over
• Children between the ages of 6 months and 5 years
• Those who are chronically ill and possibly immunocompromised

Public health implications

Since its emergence, H3N2 has contributed to a significant number of deaths worldwide during seasonal influenza epidemics. Following the 1968 pandemic, the virus has continuously evolved, altering its surface proteins (antigens) to evade immune recognition and facilitate reinfection.

As a result, H3N2 leads to more hospitalizations and deaths compared to H1N1 and influenza B viruses. To reduce the strain on healthcare systems, the development of new vaccines and therapies is essential to minimize the virus's impact and protect public health.⁴

Factors influencing evolution

Zoonotic transmission pathways

H3N2 can spread between species through zoonotic transmission. According to the WHO, humans may become infected by direct contact with infected animals or exposure to H3N2-contaminated environments. The virus evolves through amino acid substitutions, altering its genetic makeup. Since amino acids are the building blocks of proteins, these changes can modify viral proteins, including antigens. Such modifications can enable the virus to adapt and spread across different species.⁵

Antiviral resistance

H3N2 has developed resistance to adamantanes (a class of antiviral drugs) but remains susceptible to other antivirals, including oseltamivir and zanamivir. However, sporadic strains have emerged with resistance to these medications as well.

This resistance evolves because antiviral treatments eliminate susceptible strains, allowing resistant variants to survive and proliferate: a process known as "survival of the fittest."

Environmental factors

In temperate regions, H3N2 virus populations decline sharply at certain times of the year. With fewer circulating viruses, the rate of antigenic changes (mutations that help the virus evade the immune system) is limited. In contrast, densely populated tropical regions tend to have a larger and more persistent H3N2 virus population. This continuous circulation provides more opportunities for the virus to evolve and mutate, driving its adaptation over time.⁶

Surveillance and prevention strategies

Surveillance methods

Surveillance of H3N2 involves collecting and analyzing data on its activity within a population. The WHO defines three levels of surveillance:

• Passive surveillance: Data is collected from outpatient clinics and hospitals on the number of individuals infected with H3N2
• Active surveillance: Health authorities gather all reported H3N2 cases from hospitals and communities
• Sentinel surveillance: Designated reporting sites collect detailed information and biological samples from individuals suspected of having H3N2

Vaccination efforts

Vaccination plays a crucial role in preventing H3N2 infections, reducing illness severity, and protecting those around you. Ensuring vaccines are well-matched to circulating H3N2 strains enhances their effectiveness in preventing infections.

Between 2019 and 2020, influenza vaccinations were estimated to have prevented 7 million cases of influenza-associated illness, underscoring their importance in reducing disease burden.⁴

Control measures in outbreak situations

Key measures to control an influenza outbreak include:

• Vaccination to reduce infection and transmission
• Practising respiratory etiquette, such as covering your mouth and nose with a tissue or elbow when coughing or sneezing
• Minimising exposure by avoiding crowded areas and close contact with infected individuals
• Frequent handwashing and maintaining good hand hygiene
• Wearing a face mask to reduce the spread of respiratory droplets
• Using personal protective equipment (PPE) for healthcare workers to prevent infection

Future directions and challenges

Predicting evolutionary trends

H3N2 evolves rapidly, making it crucial to predict its trends for effective vaccine development each year. The virus's antigens (surface proteins recognized by the immune system) typically undergo major changes every 2–8 years. Accurately forecasting these shifts enables the timely development of updated vaccines.⁷

Improving surveillance of the virus

To enhance H3N2 virus surveillance, the following measures should be implemented:

• Public health laboratories should routinely screen specimens for influenza A
• Influenza A-positive samples should be subtyped to identify specific H3N2 variants
• Confirmed H3N2 cases should undergo contact tracing to track potential transmission routes. This helps health professionals understand how the virus spreads and assess the prevalence of person-to-person transmission, informing preventative strategies

Summary

• H3N2 is a subtype of the influenza A virus
• It first emerged in humans during the 1968 Hong Kong flu outbreak
• H3N2 rapidly evolves by altering its surface proteins (antigens), which help the immune system recognise and destroy the virus. This continuous evolution necessitates frequent updates to vaccines.
• The virus spreads through respiratory droplets from infected individuals
• H3N2 can also cross species barriers, infecting animals and humans
• Environmental factors and antiviral resistance influence the virus's adaptation and evolution
• Enhanced surveillance can help track circulating variants and identify outbreak locations
• Ongoing vaccine development is crucial for preventing H3N2 outbreaks