South African experts say the implementation of prevention strategies, combined with public engagement and collaboration between stakeholders, could significantly reduce the high rates of RSV-related morbidity and mortality in this country.
The paediatric specialists write in the SA Medical Journal that globally, the leading cause of death in children between one year and 59 months is lower respiratory tract infections, causing 18.7% of deaths per annum – most of them in Africa and South Asia.
Respiratory syncytial virus (RSV) is the commonest cause of pneumonia (20%-40%) and bronchiolitis (40%-80%) in children, particularly those under a year old.
Current management of RSV-LRTI is largely supportive and focused on alleviating symptoms, in the absence of antiviral treatment options. Children who are hypoxic are managed with supplemental oxygen.
High-flow nasal cannula oxygen has been shown to reduce the duration of hospitalisation and the need for invasive ventilation in children with moderate or severe disease, while further management includes maintaining adequate hydration and avoidance of unnecessary antibiotics, steroids and nebulisation.
The immediate goal to reduce the RSV burden is prevention of severe RSV-LRTI and RSV-associated hospitalisation.
Until recently, prevention of RSV-LRTI has largely been non-existent in low- and middle-income countries, including South Africa.
The limited use of palivizumab, a monoclonal antibody targeting site 2 of the RSV F protein, is only recommended for children at high risk of severe RSV-LRTI, and in this country, has largely been used in the private healthcare sector because of its high costs.
Furthermore, because the half-life of palivizumab is only nine to 27 days, it is logistically challenging to administer, as monthly injections are required throughout the RSV season (four to six months), which may vary geographically even within a country.
The American Academy of Paediatrics has recommended administration of palivizumab during the RSV season to infants aged <12 months who are at high risk of severe disease, i.e, those born before 29 weeks’ gestation, and to children aged <2 years with haemodynamically significant congenital heart disease or chronic lung disease of prematurity.
In 2023, the US Food and Drug Administration and the European Medicines Agency (EMA) approved the use of a new-generation long-acting monoclonal antibody and a maternal RSV vaccine as strategies to reduce the burden of RSV-LRTI in infants, both of which are being considered for licensure in SA.
Nirsevimab, a long-acting monoclonal antibody, and maternal vaccination, has been established as a key strategy for protecting pregnant women and their infants from diseases such as tetanus, pertussis, influenza and Covid-19.
A single dose attains RSV-A and RSV-B neutralising antibody levels above the putative protective threshold for at least six months, consequently only necessitating this one dose for protection throughout the average RSV season.
The efficacy of the single dose, 50mg for children weighing <5kg and 100mg for those weighing >5kg, was 78.4% (95% CI 51.9 – 90.3) in preventing RSV-LRTI hospitalisation in infants born at 29 – <35 weeks’ gestation and 76.8% (95% CI 49.4 – 89.4) in those born at >35 weeks’ gestation, through 150 days after administration.
The current cost of nirsevimab is ~$520 per dose for 50mg and 100mg doses in high-income countries, but there has been lower pricing in other countries such as Chile; tiered pricing may make it more affordable in LMICs. For SA, a dose cost of $120 results in an incremental cost-effectiveness ratio below the country’s GDP per capita.
Importantly, production capacity needs to meet the demand, particularly in LMICs, where the burden of disease is highest.
Antibodies
Vaccination is typically targeted during the second or third trimester to maximise the transfer of neutralising antibodies from the mother to the foetus. This transfer occurs through an active process where maternal immunoglobulin G (IgG) antibodies bind to the Fc receptor (FcRn) on placental cells and are then transported into the foetal circulation.
By the third trimester, antibody levels in the baby match or exceed maternal levels. However, the efficiency of this transfer can be influenced by factors such as the specific IgG subclass, antigen specificity, and maternal characteristics such as chronic infections, advanced age, high parity, a high body mass index, uncontrolled HIV infection, and hypergammaglobulinaemia.
The PREPARE RSV F nanoparticle vaccine (Novavax) was the first phase 3 maternal RSV vaccine trial – with 4 636 pregnant women receiving the RSV F vaccine or a placebo between 28 and 36 weeks’ gestation.
Although the vaccine induced high levels of anti-F IgG, the study did not meet its primary endpoint and showed a vaccine efficacy of 39.4% against medically significant RSV-LRTI and 48.3% against severe hypoxaemia-associated RSV-LRTI through 90 days, and the vaccine did not achieve licensure.
This study was followed by evaluation of an RSV pre-fusion F-protein vaccine produced by GlaxoSmithKline, the clinical development of which was terminated after observation of higher rates of preterm births (RR 1.37; 95% CI 1.08 – 1.74) in women randomised to receive vaccine (6.8%) compared with the placebo group (4.9%).
A phase 3 study of the bivalent pre-fusion F-protein vaccine (bRSV-preF) developed by Pfizer (MATISSE trial) was undertaken across 18 countries in 7 358 pregnant women at 24-36 weeks’ gestation, including 964 (13.0%) enrolled in SA.
The overall vaccine efficacy of bRSV-preF was 57.1% (95% CI 14.7 – 79.8) and 81.8% (95% CI 40.6 – 96.3) against medically attended RSV-LRTI and severe RSV-LRTI, respectively, through to 90 days after birth, with protection evident from the time of birth.
Furthermore, overall vaccine efficacy of bRSV-preF was 51.3% (95% CI 29.4 – 66.8) and 69.4% (95% CI 44.3 – 84.1) against medically attended RSV-LRTI and severe RSV-LRTI, respectively, through to 180 days after birth.
Overall, adverse events were not statistically different between the bRSV-preF and placebo groups. In the MATISSE trial, the overall preterm birth rate was similar between the vaccine group (5.6%) and the placebo group (4.7%) (RR 1.20; 95% CI 0.98 – 1.46).
Although there was no overall difference, a post-hoc analysis showed higher preterm birth rates in upper-middle-income countries among bRSV-preF vaccine recipients (7.4%) compared with placebo recipients (4.0%) (RR 1.85; p<0.05), while preterm rates were similar in high-income (5.0% v. 5.1%), lower-middle-income (3.1% v. 5.9%) and low-income (2.6% v. 2.5%) countries.
Most preterm births were late preterm births at 35-36 weeks’ gestation with no increase in mortality. Importantly, in both SV efficacy trials, preterm births were not linked to the timing of vaccine administration, and occurred >30 days after vaccination, and only in specific countries. Preterm births also did not correlate with gestational age at vaccination.
Differences in preterm births between vaccine and placebo groups coincided with the surge in Delta and Omicron SARS-CoV-2 variants, but the biological basis for this finding remains unexplained.
The bRSV-preF vaccine (ABRYSVO) was therefore licensed in the USA in 2023, indicated for vaccination of pregnant women at 32 and 36 weeks’ gestation, owing to the statistically non-significant imbalance in preterm births in the bRSV-preF recipients, most of which were late preterm.
In contrast, the EMA and the UK have approved the use of bRSV-preF in pregnant women at 24-36 weeks’ gestation.
Important considerations regarding the bRSV-preF vaccine in pregnant women in SA include the need for data on immunogenicity and transplacental transfer of antibody in women with HIV.
HIV-exposed uninfected infants have lower concentrations of maternally acquired RSV neutralising antibody, in the absence of vaccination, which predisposes them to higher rates of RSV-LRTI hospitalisation compared with HIV-unexposed infants.
Maternal hypergammaglobulinaemia due to HIV can reduce the efficiency of transplacental antibody transfer. Notably, this needs to be explored in the context of women on long-term antiretroviral therapy.
The immunogenicity of bRSV-preF and transplacental efficiency of transfer are currently being evaluated in women with HIV in South Africa.
Recommendations for RSV prevention in SA
Maternal RSV vaccination and administration of nirsevimab to infants or high-risk children aged <2 years would substantially reduce the burden of RSV in SA, including hospitalisations and mortality.
These two highly effective preventive strategies are cost effective, but there are some anticipated challenges in the local context. Both are currently awaiting approval from the South African Health Products Regulatory Authority, which would be followed by recommendations by the National Immunisation Technical Advisory Group.
Implementation of these strategies will largely be based on the availability of each product, and the delivery pathways in private and state-funded facilities.
In principle:
• Nirsevimab should be made available to all infants under 12 months, and to high-risk children between one and two years of age immediately preceding and during the RSV season
.• All pregnant women are to be offered the maternal RSV vaccine, year-round, to limit the programmatic challenges of delivery and to provide protection in instances of seasonal variability. In unvaccinated women or preterm newborns (<37 weeks), or if the baby is born within a month of the mother receiving her RSV vaccine, nirsevimab should be provided.
Last month, the WHO Strategic Advisory Group of Experts (SAGE) on Immunisation made the following recommendations:
• all countries should introduce passive immunisation for the prevention of severe RSV disease in young infants,
• The decisions to include the maternal RSV vaccinate and/or the long-acting monoclonal antibody would need to consider the cost, financing, supply, anticipated coverage and feasibility.
• a single dose of maternal RSV vaccine should be administered in the third trimester of pregnancy and post-marketing surveillance would be necessary.
RSV is now a preventable disease in infants and high-risk children, and access to these effective interventions is urgently needed for children in South Africa.
Study details
The dawn of preventing respiratory syncytial virus lower respiratory tract infections in children
Z Dangor, S A Madhi, H J Zar, D Demopoulos, on behalf of the South African Paediatrics Association
Published in the SA Medical Journal in October 2024
Respiratory syncytial virus (RSV) is the commonest cause of lower respiratory tract infection (LRTI) in children, particularly those aged <1 year. In South Africa (SA), increased hospitalisation rates during the RSV season, including access to intensive care facilities, place a huge burden on the healthcare system. Furthermore, RSV-LRTI during early childhood may lead to long-term respiratory sequelae, including recurrent wheezing, asthma, and impairment of lung function. Recently, two new RSV prevention strategies have emerged: nirsevimab, a long-acting monoclonal antibody, and a maternal RSV vaccine. Both strategies have shown high efficacy in reducing RSV-LRTI hospitalisation in infants and are being considered for licensure in SA. Implementation of these prevention strategies, combined with public engagement and collaboration between stakeholders, could significantly reduce RSV-related morbidity and mortality in SA.
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