Respiratory tract infections continue to impose a substantial global disease burden, with lower respiratory tract infections remaining the leading cause of death worldwide. According to 2021 data from the Global Burden of Disease study , mortality from lower respiratory tract infections reached 28.7 per 100,000 population. COVID-associated cases were not included. Lower respiratory tract infections are ranked as the seventh leading cause of death globally, with human pneumoviruses responsible for most cases.

Respiratory syncytial virus (RSV) accounted for an estimated 3.3 million lower respiratory tract infections in children younger than 2 years in 2019 and for 101,400 deaths among children younger than 5 years. Human metapneumovirus (HMPV) caused approximately 502,000 lower respiratory tract infections in children younger than 5 years of age in 2018. In nursing home settings, RSV and HMPV infections have been shown to increase mortality and morbidity among older adults.

Given this high disease burden, efforts to develop safe and effective vaccines against RSV and HMPV have increased. This review summarizes the status of vaccine development against human pneumoviruses, with relevance for clinicians caring for pediatric, older adult, and other high-risk populations.

Inactivated RSV Vaccines

The first RSV vaccine evaluated in humans was developed in 1960 using monkey kidney tissue and formulated as a formalin-inactivated RSV vaccine. In children, this vaccine leads to enhanced respiratory disease (ERD) after natural RSV infection. Serologic analyses showed that vaccinated children developed RSV-binding antibodies, but neutralizing and fusion-inhibiting responses were weak. Postmortem tissue samples from individuals who died from ERD revealed immune complex deposition and complement activation, suggesting that poorly functional antibodies may have increased the risk for severe disease.

Decades later, a purified beta-propiolactone-inactivated RSV vaccine (BPL-RSV) was developed with the addition of TLR9 and NOD2 receptor ligands and evaluated in BALB/c mice. The vaccine effectively activated antigen-presenting cells in vitro and induced a local immunoglobulin A response. Mucosal immunization resulted in an enhanced T helper type 1-immunoglobulin G2a response in vivo. The addition of TLR9 and NOD2 ligands promoted affinity maturation of RSV-specific immunoglobulin G antibodies and shifted the T cell response toward increased interferon-gamma production, consistent with a T helper type 1-dominant profile.

ERD was not observed after the administration of BPL-RSV. Further studies are required to reach definitive conclusions regarding its efficacy and safety.

RSV Subunit Vaccines

In animal models, antibodies directed against the RSV fusion protein have demonstrated protective activity against RSV infection. These findings led to the development of the humanized monoclonal antibody palivizumab in the 1990s for RSV prevention in high-risk children, followed by nirsevimab in July 2023.

In primate models, genetically engineered chimeric F-G glycoprotein subunits were not associated with ERD. However, their protective efficacy in vulnerable populations has been limited.

A breakthrough in RSV subunit vaccine development followed the work of McLellan and colleagues, who identified the stabilization of the metastable prefusion conformation of the F fusion protein. Several RSV subunit vaccines targeting the pre-fusion state have since been developed. Two have been approved in the US for the prevention of RSV-associated lower respiratory tract disease.

AREXVY (RSVPreF3 OA)

On May 3, 2023, the first RSV vaccine for adults aged 60 years or older — and subsequently for adults aged 50-59 years with an increased risk for RSV-associated lower respiratory tract disease — was approved by the FDA. AREXVY is a single-dose intramuscular subunit vaccine based on the stabilization of the RSV A2 F protein in its trimeric prefusion form combined with the AS01E adjuvant system.

In a phase 1/2 study that included younger and older adults, the highest RSVPreF3 dose combined with AS01E demonstrated good immunogenicity and an excellent safety profile.

In a phase 3 study, maternal immunization with this vaccine prevented infection in newborns for up to 6 months. The study was discontinued in February 2022 after concerns arose regarding a higher preterm birth rate among vaccinated individuals.

In later-stage evaluations, RSVPreF3 OA showed an acceptable safety profile over one RSV season in older adults, with one reported case of Guillain-Barré syndrome and high efficacy against RSV-associated lower respiratory tract disease (82.6%), severe RSV-associated lower respiratory tract disease (94.1%), and RSV-associated acute respiratory disease (71.7%). Efficacy was consistent across RSV subtypes and underlying comorbidities.

An observational study of adults older than 64 years conducted between May 2023 and July 2024 identified an increased risk for Guillain-Barré syndrome within 42 days of AREXVY vaccination. However, a causal relationship could not be established.

ABRYSVO (RSVpreF)

ABRYSVO, a bivalent prefusion F vaccine approved in the US in May 2023, contains 60 µg of trimeric F glycoprotein from the major RSV subgroups A and B. It is indicated for active immunization during pregnancy at 32-36 weeks’ gestation, for adults aged 60 years or older, and for adults aged 18-59 years with an increased risk for RSV-associated lower respiratory tract disease.

Phase 1/2 studies have demonstrated good safety, tolerability, and immunogenicity. The addition of aluminum hydroxide or CpG aluminum hydroxide did not provide clinical benefit in adults or healthy older adults.

In phase 2 studies, ABRYSVO achieved 86.7% efficacy in preventing symptomatic RSV infection in adults and demonstrated efficient transplacental antibody transfer when administered during the late second or third trimester.

In a phase 3 study, maternal immunization between 24 and 36 weeks of gestation resulted in an efficacy of 81.8% at 90 days and 69.4% at 180 days in preventing severe lower respiratory tract infections in infants.

Live Attenuated Vaccines

Live attenuated vaccines offer several advantages for pediatric use. They are not prime for ERD but stimulate systemic and local immune responses, including innate, humoral, and cellular immunity. Intranasal administration is feasible, and replication in the upper respiratory tract of young children can occur, even in the presence of maternal antibodies.

Several live attenuated RSV vaccine candidates have been developed. Pooled data from seven phase 1 studies suggest an estimated efficacy of 67% against severe RSV infection and 88% against severe lower respiratory tract infection.

One particularly promising candidate, RSV/ΔNS2/Δ1313/I1314L, is currently under phase 3 evaluation. The RSV/ΔNS2/Δ1313/I1314L is generated from a combination of deletion of the NS2 gene and codon 1313 in the L gene with substitution of leucine by isoleucine in the RSV A2 genome. In clinical studies involving children aged 6-24 months, intranasally administered vaccines have shown good immunogenicity. Incorporation of four amino acid substitutions from RSV strain Line 19 (I79M, K191R, T357K, and N371Y) improved stability and manufacturing scalability.

Combined RSV and HMPV Vaccines

Although RSV is the primary focus of pneumovirus vaccine development, efforts to develop HMPV vaccines have been ongoing since 2001. To date, no HMPV vaccine has been approved yet. However, combined HMPV-RSV and HMPV-human parainfluenza virus type 3 (HPIV3) vaccines are currently undergoing clinical trials.

Among the best-known bivalent candidates are the messenger RNA (mRNA) vaccines, mRNA-1365 and mRNA-1653. mRNA-1365 targets RSV and HMPV, and cases of ERD after vaccination have been reported.

mRNA-1653 is the first messenger RNA vaccine designed to prevent both HMPV and HPIV3 infections. It encodes two distinct nucleoside-modified mRNAs, a full-length HMPV fusion protein and an HPIV3 antigen, co-formulated in lipid nanoparticles.

Phase 1 evaluations in healthy adults and children aged 18-55 months showed an acceptable safety profile and increased neutralizing antibody titers against both viruses after a single intramuscular dose.

Conclusion

RSV and HMPV are well-characterized human pathogens that can cause life-threatening diseases and substantial disease burden in vulnerable populations, particularly infants and older adults. Efforts to implement preventive strategies have led to the development of monoclonal antibodies and structure-based vaccines that have demonstrated favorable safety and efficacy profiles for the prevention of severe RSV infection in clinical trials. Further research is required to expand vaccine availability, especially for children and populations in low- and middle-income countries.

This story was translated from Univadis Germany, part of the Medscape Professional Network.