A new era for care of respiratory infections in India: The respiratory syncytial virus story

The history of scientific advancement in the prevention and treatment of respiratory syncytial virus (RSV) in infants and young children is unique in more ways than one. Although the virus was discovered in the 1950s and efforts towards its prevention ensued over 60 years ago, a practicable strategy was approved for use only in the late 1990s.^[1] Palivizumab, a monoclonal antibody for passive prevention in high- risk infants, has been available in the market of high-income countries for 25 years, but the drug actually entered India barely a year ago. This was soon replaced by the longer half-life drug, Nirsevimab, in late 2025.^[2] The vaccine for use in pregnant women (targeted at the prevention of disease in young infants) is yet to be approved for use in India. In fact, the majority of the low-middle-income countries (LMIC) do not have access to any of the above strategies for RSV prevention. This is ironic since a major proportion of RSV associated with lower respiratory infections occurs in LMIC.^[3]

The highest burden of RSV infection is in infants <6 months of age (incidence of approximately 96 per 1000 children per year). This age group constitutes nearly half of all RSV-related hospital admissions for lower respiratory tract infection (LRTI), and 45% of RSV-related deaths.^[4] Data on neonatal RSV is most likely under-reported owing to its overlapping clinical presentation with other neonatal morbidities. It presents as a sepsis-like illness and apnea in a newborn. Although most infections occur in otherwise healthy children, nearly 1/5th of all life-threatening RSV infections are in those who have co-morbidities. RSV disease is highly variable across geographic regions, with almost 3 times the incidence of lower respiratory disease being reported from LMIC. On the contrary, hospitalisation rates are lower in LMICs, likely due to inadequate health care access. Many of the deaths (70%) shockingly occur outside of the hospital settings in low-income countries.^[5]

The advent of polymerase chain reaction and rapid diagnostics with point-of-care molecular diagnostics has made recognition easier, but these tests are not uniformly available across regions and are often expensive. One might argue against the need for confirmation of disease since there is no direct therapeutic benefit. But affirmation leads to accurate reporting of disease burden; it more importantly helps prevent overuse of antibiotics in RSV LRTI.^[6]

Therapy is purely supportive. Several strategies have been tried, including bronchodilators, steroids, leukotriene antagonists, hypertonic saline nebulisations, ribavirin, antibiotics, chest physiotherapy and high flow nasal gases. None of these is supported by evidence.^[5] Clinicians need to optimise hydration with gavage feeds or intravenous fluids if oral feeding is inadequate. Oxygen therapy is the mainstay of RSV LRTI management, with levels of support based on the severity of illness.

The above reasons (non-specific presentation, high disease burden, chances of hospitalisation and mortality, no real therapeutic choices) make prevention of RSV the sole important health improvement strategy in this regard. The disease is known to affect children beyond 6 months as well, and also has an association with long-term negative effects on lung health (asthma, recurrent wheeze).^[7] However, the highest priority of such measures should target infants <6 months of age, and other young children who are at high risk of morbidity from viral LRTI.

Measures toward RSV prevention revolve around understanding the F protein. This viral membrane protein is responsible for the fusion of the virus with its target cell. Hence, any “drug” that deactivates or induces antibody production against this protein prevents viral fusion with human cells and halts entry into the host cell.^[5]

The history of RSV prophylaxis began with a calamity.^[1] The first developed formalin-inactivated vaccine resulted in enhanced respiratory distress when RSV disease developed post vaccination; this led to several hospitalisations and the death of 2 children. It took immense effort to understand the structure of the Fusion glycoprotein, which is unstable in its pre-fusion state but highly stable in its post-fusion conformation. The neutralising antibody epitopes are located on the pre-fusion conformation. Research to stabilise the Pre-F- glycoprotein ensued. This resulted in the development of 2 important prophylactic strategies, i.e., RSV-pre-F vaccine that is given antenatally between 24-36 weeks of gestation to increase antibody production in maternal serum, which is transferred transplacentally to the vulnerable infant (when born at least 2 weeks after vaccination),^[8] and monoclonal antibody given to the neonate/young infant for passive protection. The latter strategy is an unprecedented immunisation practice for any other respiratory illness.^[9]

The bivalent RSV-pre-F maternal vaccine contains stabilised pre-Fusion conformation protein of RSV A and B. Phase 3 clinical trials have found the vaccine to be effective in preventing RSV-confirmed LRTI (51•3%, 95•78% confidence interval (CI) 29•4 to 66•8) and severe RSV-confirmed LRTI (69•4%, 95•78% CI 44•3 to 84•1) until 6 months after birth. In 2024, this RSV-pre-F maternal vaccine received market authorisation for use in 44 countries.^[8] Argentina successfully implemented its use through the effective involvement of policymakers and awareness amongst the public and medical community. There has been some concern about the association of maternal vaccination with preterm delivery; this requires further post-marketing studies in those countries that adopt this strategy. Since LMICs are underrepresented in studies pertaining to maternal RSV-pre-F vaccines, World Health Organisation (WHO) prequalification would be needed before Gavi (Vaccine Alliance) can fund its purchase for those countries that qualify.^[9]

Early work on intravenous immunoglobulin against RSV for prevention of serious RSV LRTI was on preterm infants with bronchopulmonary dysplasia (BPD). Success associated with its use for passive immunisation prompted further research.

Palivizumab is a humanised monoclonal IgG antibody (MAB) developed against the A antigenic site of the F protein. It was introduced in 1998 and was considered effective. However, it has a short half-life and needs to be administered intramuscularly every month throughout the RSV season. Although it entered the Indian market a year ago, its supply has been stopped and replaced by Nirsevimab. This MAB has an extended half-life and is directed against the Ø epitope on the pre-F RSV F protein. It is efficacious against very severe RSV- LRTI (78•6%, 95% CI 48•8–91•0), and RSV LRTI requiring hospitalisation (76•8%, 95% CI 49•4–89•4); up to 150 days after injection. Several countries have introduced Nirsevimab into their immunisation programmes (the USA, Spain, Luxembourg, Italy, and France). Clesrovimab is a new extended half-life monoclonal antibody in development and testing stages.^[9]

The Centres for Disease Control recommends that all infants be protected against RSV by either the active method using maternal vaccination or the monoclonal antibody for passive protection throughout the high-risk season. It is important to emphasise that in countries near the equator and subtropical areas, the seasonality of disease is not well defined. The infection can occur year-round.^[10] Therefore, the WHO recommends prophylaxis immediately after birth for term infants and high-risk infants year-round in these regions.^[11]

The National Neonatology Forum India endorses this recommendation but currently advises the use of Nirsevimab in high-risk infants (BPD, congenital heart disease, post-tracheostomy, Cystic fibrosis, congenital immunodeficiency, neuromuscular disorders). Parents of low-risk term infants can indeed be informed about this preventive drug for shared decision-making. The maternal vaccine is not yet available in India.^[2]

Reports of immense success in the prevention of serious RSV-related illness and mortality with the above vaccines/passive immunisation strategies must prompt their use in India on a wider scale. A staged approach of first providing these at affordable prices to high-risk infants, followed by large-scale universal use, is desirable. The drugs are out there; coordinated efforts by medical professionals, stakeholders and political leaders would go a long way in decreasing disease burden and possibly in improving long term lung health.