Quick quiz. Name a virus that causes millions of lung and respiratory tract infections globally – but isn’t flu, SARS-CoV-2, or the common cold.
Clue: We have no vaccine or antiviral available.
Introducing human metapneumovirus (HMPV), probably the most important virus almost nobody talks about.
Unexplained illnesses and the discovery of a novel virus
In 2001, Dr. Bernadette van den Hoogen and colleagues at the Erasmus Medical Center in Rotterdam were investigating unexplained respiratory illnesses in children. Using techniques like random PCR amplification, virus cell culture, and electron microscopy, these researchers discovered a novel virus.
Comparing the genetic sequences of their novel virus to available databases, van den Hoogen and the team found their mystery respiratory virus most closely matched the genetics of avian metapneumovirus (AMPV) – a virus that infects birds, causing respiratory diseases like turkey rhinotracheitis and swollen head syndrome in chickens. Thus, they named their discovery human metapneumovirus (HMPV). Their findings were published in the journal Nature Medicine in 2001.
HMPV had been around for a while
No, HMPV’s patient zero wasn’t a 1990s farmer with a poultry problem.
In their 2001 study, van den Hoogen and colleagues analyzed stored samples from children with respiratory tract infections that had previously been unexplained. The oldest samples they looked at dated back to 1958, which led them to conclude that HMPV had been circulating in the human population for at least five decades prior to its identification.
It came from birds
The avian version of this virus can be divided into four subgroups, AMPV-A to D. Subgroup C of AMPV shares the closest relationship with HMPV. This suggests that HMPV evolved from AMPV-C. Tracing AMPV-C leads us to turkeys and ducks, the primary vectors for AMPV-C. But AMPV-C can also infect other birds (e.g., chickens, pigeons, guinea fowl, pheasants, quails, and geese).
When did it jump to humans?
In 2008, advanced statistical methods were applied to trace the development and spread of HMPV. By examining changes in the virus’s genetic material over time, the team concluded that HMPV and AMPV-C shared a common ancestor about 200 years ago, with cross-species (from bird to human) transmission occurring about this time.
Some imagined patient zeros
So, while we’ll never know the exact origin of HMPV, the available evidence suggests AMPV-C made a leap of faith from an infected bird into its first human host.
Perhaps it was in 1803 that George, a poultry farmer in rural England, developed a persistent cough and fever after cleaning his barn – his wife treating him with homemade herbal teas until he recovered several weeks later. Or perhaps in 1811, Louis, a fur trapper in Quebec who uses birds as bait. This winter, he develops a high fever and chills after handling infected waterfowl. Local tribal healers use native herbs to treat his severe flu-like symptoms.
Symptoms, seasonality, and spread
Symptoms of HMPV mimic those of other respiratory viruses, including cough, runny nose, sore throat, shortness of breath, and fever. Severe cases can lead to bronchiolitis or pneumonia, and HMPV is a leading cause of severe childhood pneumonia. In temperate regions, HMPV is most active from late winter through early spring, spreading through coughing, sneezing, close contact, and contaminated surfaces. The incubation period ranges from 3 to 6 days.
Who’s at risk?
While most HMPV cases are mild, certain groups are at higher risk for severe illness, including young children, the elderly, and those with weakened immune systems. Nearly all children are infected by the time they are 5 years old, with premature infants being particularly vulnerable.
Vaccine development
Currently, there is no approved vaccine for human metapneumovirus (hMPV), although research is ongoing. Developing an HMPV vaccine is challenging due to the risk of vaccine-enhanced disease, a phenomenon where vaccination with inactivated viruses can lead to more severe illness upon subsequent exposure. This issue was historically observed with inactivated RSV and measles vaccines in the 1960s, which resulted in severe respiratory diseases in vaccinated children upon encountering the actual virus.
Animal studies have shown that inactivated hMPV vaccines can sometimes cause enhanced disease after exposure to the virus. This occurs when the immune response induced by the vaccine is inadequate, leading to an exaggerated inflammatory reaction during infection.
Despite these challenges, researchers are exploring various strategies to develop a HMPV vaccine, including live-attenuated and protein subunit vaccines. Moderna is currently running a Phase I trial to evaluate the immune response in children to two investigational vaccines (mRNA-1345 and mRNA 1365) they hope will protect against RSV and HMPV.
Prevention
Until there is a vaccine or antiviral, preventing HMPV infection relies on practices similar to those used during the COVID-19 pandemic: frequent handwashing, avoiding touching the face with unwashed hands, cleaning surfaces regularly, covering coughs and sneezes, and staying away from others when sick.
Treatment
Most HMPV cases resolve on their own, with supportive care. Severe cases, especially in infants, may require hospitalization and mechanical ventilation. There is no specific antiviral therapy for HMPV, though Ribavirin, used for RSV and Hepatitis C, has been used in severe HMPV cases, sometimes with intravenous immunoglobulin.
Genome and surface proteins
The HMPV genome consists of RNA with eight genes encoding nine proteins. The virus is enveloped by a lipid membrane with three viral proteins projecting from its surface. Two of these proteins, the G protein and the fusion (F) protein, facilitate the virus’s attachment and entry into target cells.
Lineages
HMPV is categorized into two main groups, A and B, each with several subgroups. These groups differ primarily in the F and G proteins, with the F protein remaining similar across types, while the G protein varies significantly.
The F protein and cell entry
The F protein is essential for fusing the viral membrane with the target cell membrane, allowing viral entry. It can also cause the fusion of infected cells into a syncytium, a hallmark of HMPV and RSV infections.
HMPV in cell culture
The F protein is initially inactive and is activated by host proteases. In the lab, trypsin is added to activate the F protein, facilitating HMPV infection. Diagnosis of HMPV often relies on PCR assays due to the virus’s slow growth in culture, requiring multiple passages to produce detectable signs of infection, which can lead to mutant variants.
HMPV in the post-COVID era
During the peak of the COVID-19 pandemic, stringent measures such as social distancing, mask-wearing, and lockdowns significantly reduced the transmission of various non-SARS-CoV-2 infectious diseases worldwide. However, as these measures were lifted, a resurgence in infections, including HMPV and influenza, has been observed globally.
For example, a Japanese study surveying 18 hospitals in Hokkaido Prefecture identified a dramatic increase in HMPV hospitalizations from July 2022 to June 2023 (12 months), with a peak of 27 hospitalizations per week and a total of 317 patients, primarily children aged 3–6. This marked resurgence followed a period from March 2020 to June 2022 (28 months), where only 13 hMPV hospitalizations were recorded.
Similar trends can be seen on The National Respiratory and Enteric Virus Surveillance System (NREVSS) dashboard. NREVSS is a surveillance system, with participating US laboratories reporting weekly test data for HMPV and other viruses. In recent years, the peak percentage positive values for these US labs for HMPV testing have been: 2020 (7%), 2021 (0.3%), 2022 (8%), 2023 (11%), and 2024 (8%, so far).
HMPV Research at VRS
At VRS, we specialize in growing and analyzing HMPV strains in various cell culture systems, including traditional monolayers and three-dimensional air-liquid interface (ALI) cultures that better mimic the human respiratory system.
If you need any type of virus testing services or consultancy, reach out to our team, and an experienced virologist will get back to you right away.
Further reading
If you’d like to learn more, we recommend our blog articles on ALI culture and how we use ALI to study HMPV’s cousin, RSV.
