The early signs of H3N2v in humans include fever, cough, fatigue (extreme tiredness), and less commonly, gastrointestinal (GI) issues (e.g. vomiting, and diarrhoea), eye redness or eye itchiness. 

Read on to find out why it is important to recognise these seemingly ‘mild’ symptoms, what H3N2v is, how it is transmitted to humans, how certain treatment drugs target H3N2v, whether you are included in the high-risk group category of H3N2v infection, and much more! 

Introduction

What is H3N2v?

H3N2 is a non-human type A influenza virus that usually infects swine (pigs). When it transmits from swine to humans, it is referred to as ‘’H3N2 variant virus’’ or H3N2v, for short.¹ 

What do H and N stand for in H3N2?

The H and N in the term stand for hemagglutinin and neuraminidase, respectively. Hemagglutinin and neuraminidase are glycoproteins (proteins with carbohydrate-based glycan groups) that coat the outer membrane of influenza viruses.² They work together and enable influenza viruses to enter the host (in this case, swine) and cause infection.

What do the numbers in H3N2 represent? 

Influenza A viruses are divided into different subtypes based on the antigenic properties (the way in which they trigger a human immune response) of hemagglutinin and neuraminidase.² 

There are over 16 hemagglutinin (H1-H16) and 9 (N1-N9) neuraminidase subtypes that have been identified so far. This is what makes H3N2 different from H3N1 or H1N1 (‘’swine flu’’), despite both influenza subtype A viruses mainly circulating in swine. 

When was the first case of H3N2v identified?

The first case of H3N2v in humans was identified in July of 2011 in the United States.¹

Why is it important to recognise the early signs in humans?

It is very important to recognise the early signs of H3N2v because, as will be discussed shortly in further detail, it usually manifests with mild symptoms³ that are often experienced in typical seasonal human flu, thus potentially causing some patients to dismiss the symptoms. As H3N2v progresses, however, it can result in patients being hospitalised or even dying.¹ In fact, in 2012, when the United States experienced the largest H3N2v outbreak, 16 out of 306 infected people were hospitalised (5.2%) and 1 tragically, died (0.3%). 

Understanding H3N2v transmission

H3N2 spread to swine 

The mechanism by which H3N2 enters swine before it is transmitted to humans is very complex but in brief, simplified terms it occurs as follows:²

1. Hemagglutinin binds to sialic acid receptors of glycoproteins and/or glycolipids found on the cell-surface of the host (swine)
2. Hemagglutinin fuses with the host cell membrane and enters the interior of the host cell where it starts to replicate 
3. Neuraminidase cleaves (cuts) the sialic acid residues from the infected cell surfaces of the host 
4. Newly-made viruses are released from the host cell, leading to more host cells being infected and further spread of the infection

H3N2v transmission from swine to humans

According to the scientific literature, the most common way in which H3N2v is transmitted from swine to humans is via direct (69%) or indirect (29%) contact with infected swine at farms or agricultural fairs.¹ Thus, farmers who raise pigs, workers in the swine industry, and children who live near areas with swine are suggested to be at the highest risk.³ 

H3N2 can transmit³ from swine to humans directly or indirectly when people:

• Unknowingly, inhale cough or sneeze air droplets from infected swine (indirect)
• Touch their nose, mouth, or eyes after touching infected surfaces (direct) 

Pork consumption and H3N2v infection 

To date, there have not been any cases reported where H3N2v was caused by eating pork or pork products.³ This, however, does not mean that pork from affected pigs should be consumed as there are likely to be other risks involved, such as foodborne illnesses. 

Human-to-human H3N2v transmission 

Although not as common, there are cases in which H3N2v has been reported to spread between humans, particularly in the winter months where the risk of influenza transmission is highest.⁴ 

Early signs of H3N2v infection

Symptoms commonly associated with H3N2v

Similar to the typical human seasonal flu, the main early signs and symptoms of H3N2v are generally mild and include:¹

• Fever (98%)
• Cough (85%) 
• Fatigue or lethargy (83%)

Less common signs and symptoms of H3N2v include:^1,4

• Vomiting
• Diarrhea
• Eye redness or eye irritation

Risk factors and vulnerable populations

Groups at higher risk of H3N2v infection

Coupled with the poor prognosis of patients with severe H3N2v, another major reason as to why recognising the early signs of H3N2v is imperative is because children and adolescents under 18 years of age, with a median age of 5-6 years appear to be the groups at highest risk of H3N2v, as demonstrated in research studies.¹

Other groups thought to be at high risk³ of H3n2v infection include:

• People aged 65 years and older
• People who are pregnant
• People with certain medical conditions including:¹
  • Asthma (16%)
  • Chronic lung diseases (1.8%)
  • Neurological and neurodevelopmental conditions (1.8%)

• People with weakened immune systems including:
  • Diabetic patients 
  • Cancer patients on cancer treatment 

Factors contributing to increased susceptibility

In addition to age, health and immune status as well as environmental factors, there are other factors that are thought to contribute to increased susceptibility to H3N2v infection. These include:⁵

Genetic mutations (“antigenic drift’’) in H3N2v

H3N2v can gradually change or substitute some of the amino acids (“amino acid substitution’’ which is a type of point mutation where one amino acid is replaced with another) in its hemagglutinin and/or neuraminidase surface proteins. This process, referred to as “antigenic drift’’, acts as the main way in which H3N2v and other influenza viruses generate new influenza variant viruses and evade the human immune response.

In fact, antigenic drift is suggested to be the main reason as to why different influenza variant viruses develop resistance against certain drugs (drug resistance), making it necessary for new drugs to be developed every year to tackle the annual influenza outbreaks.

Viral reassortment (‘’antigenic shift’’)

H3N2v, like many other influenza viruses contains a fragmented or ‘’segmented genome’’, which allows it to generate new viral strains/subtypes by exchanging some of its RNA segments between other influenza viruses. This process is known as ‘’reassortment’’ or ‘’antigenic shift’’ and is another effective way in which H3N2v can evade the immune response and enhance virus transmission.

Interestingly, reassortment is actually what resulted in the generation of H3N2 in the first place when H2N2 and avian (bird) viruses exchanged some of the genes in their neuraminidase (N2) and hemagglutinin (H3) proteins together, respectively.² 

Diagnostic methods for H3N2v

At present, there is no specific test to diagnose³ H3N2v. Like any other viral infection or disease, healthcare providers diagnose H3N2v mainly based on symptoms. In some cases, however, respiratory specimens such as a nasal swab or throat swab may be ordered and sent to laboratories for further testing. 

Treatment Methods for H3N2v

At present, there are several FDA-approved antiviral drugs⁶ that are currently used to treat H3N2v including:

• Oseltamivir phosphate: administered orally and is safe for use in people aged 14 years and over 
• Zanamivir (oral inhalation): administered via oral inhalation and is safe for use in people aged 7 years and over. Zanamivir, is however, not recommended for people with breathing problems including asthma or chronic obstructive pulmonary disease (COPD)

How do these antiviral drugs work to treat H3N2v?

Oseltamivir phosphate and zanamivir work by targeting the ‘’active site’’ or region of neuraminidase (enzyme) where sialic acid residues (substrates) bind to before being cleaved,² thus preventing the completion of the H3N2 infectious cycle and further spread of infection. 

Prevention strategies

Vaccination recommendations

Whilst antiviral drugs⁶ can be effective in treating H2N3v, they cannot prevent H2N3v and therefore are not a substitute for seasonal flu vaccination. 

The CDC³ recommends people aged 6 months and older as well as people who have contact with swine get a seasonal flu vaccination every year. 

However, it is important to note that seasonal flu vaccines may not be able to offer direct protection against H2N3v, but they may help prevent H3N2v transmission from humans to swine, in turn potentially decreasing the likelihood of reassortment occurring in swine and the generation of new influenza variant viruses that may result in flu pandemics.¹

Hygiene practices and behavioural precautions

In addition to getting the seasonal flu vaccine annually, there are several hygiene practices and behavioural precautions⁷ that may help prevent H3N2v infection and its further transmission between humans and swine. These include:

• Avoiding contact with swine, food or drink consumption, and touching the mouth, nose, or eyes in swine barns at agricultural fairs: especially if included in the above-mentioned high-risk group category and/or experiencing flu symptoms 
• Washing hands thoroughly with soap and water or using an alcohol-based hand sanitiser before and after exposure to swine 
• Wearing protective equipment such as gloves, a face mask or a respirator if working around infected people and/or swine 

Summary

H3N2v is a rare type A influenza (H3N2) variant virus (denoted by the lowercase ‘’v’’) that is mainly transmitted from swine to humans. Therefore, people with direct or indirect exposure to swine, particularly children and adolescents under 18 years of age as well as swine workers, are at high risk of H3N2v infection. 

In brief and very simplified terms, the transmission infectious cycle of H3N2 involves viral entry (via hemagglutinin), release, and subsequent infection (via neuraminidase) of swine.

Swine may then transmit H3N2 to humans through cough or sneeze air droplets (indirectly) or via infected surfaces (directly). 

The most common early signs and symptoms that are used to diagnose H3N2v in humans include: 

• Fever
• Cough
• Fatigue 

Despite seemingly ‘mild’, there are many reasons as to why it is important to recognise these early signs and symptoms and seek treatment immediately, including:

• H3N2v can result in hospitalisation and even death, in severe cases 
• H3N2v can generate new variant viruses, strains, or subtypes that may develop resistance against certain drugs and cause flu pandemics by either: 
  • Substituting some of the amino acids in its hemagglutinin and/or neuraminidase surface proteins over time (‘’antigenic drift’’) 
  • Exchanging some of its genes with other influenza viruses in the host (‘’antigenic shift’’ or ‘’reassortment’’)

At present, H3N2v is mainly treated via antiviral drugs such as oseltamivir phosphate and zanamivir, both of which work by targeting the active site of neuraminidase. 

Good hygiene practices such as washing hands thoroughly with soap and water as well as avoiding touching the nose, eyes, or mouth after exposure to swine, are essential to prevent H3N2v infection and further transmission.