Protecting our future: call for respiratory syncytial virus vaccine trial in infants

Highlights

• Raise awareness about the significant impact of respiratory syncytial virus (RSV) infections on both adults and children, highlighting the considerable illness and mortality caused by the disease.

• Emphasize the current challenges in developing a reliable and safe RSV vaccine despite extensive research on epidemiology, clinical features, and diagnostic methods.

• Highlight the exclusion of infants in recent trials for an RSV vaccine despite the substantial burden of RSV infections they face, particularly in low- and middle-income countries (LMIC).

• Illustrate the limitations of existing preventive measures, such as Palivizumab, in effectively reducing mortality and morbidity associated with RSV infections in children.

• Make use of targeted strategies used by LMICs like Ethiopia and Zambia in the past. Use WHO tools and community health workers to prioritize and distribute vaccines, advocating RSV immunization through grassroots education by healthcare providers for widespread infant coverage, aiming to reduce mortality, decrease morbidity, optimize resource allocation, and achieve cost savings.

Respiratory syncytial virus (RSV) is one of the most significant infectious diseases affecting adults and children, leading to considerable illness and death¹. The primary pathological features of RSV infection include acute bronchiolitis, inflammation, and blockage of airway lumens due to the presence of cellular debris of epithelial cells, mucin, fibrin, and macrophages^1,2. An epidemiological study conducted between 2000 and 2020 found a median of 1641 [interquartile range (IQR) 552–2415] RSV cases per season worldwide³. Most cases (55%) occurred in infants under one year, while 8% were in individuals aged 65 and older³. Data on subtyped RSV cases were provided by six countries: the Czech Republic, the Netherlands, New Zealand, Portugal, Singapore, and South Africa. Together, these countries reported 6148 cases, with 51% identified as RSV A (3155 cases) and 49% as RSV B (2993 cases)³. Despite extensive research on its epidemiology, clinical features, and diagnostic methods, a reliable and safe vaccine remains elusive¹.

In 1996, the first inactivated RSV vaccine was introduced, but recipients experienced severe disease. Until 2023, no effective treatment existed. Arexvy and Abrysvo vaccines were developed then. After a successful trial, the FDA recommends a single dose of RSVpreF OA recombinant vaccine for adults over 60 to prevent RSV-related respiratory infections and severe lower respiratory tract diseases in adults aged 60 or older^4,5. The trial found vaccine’s efficacy against real-time polymerase chain reaction (RT-PCR)–confirmed RSV-related lower respiratory tract disease was 82.6% (96.95% CI, 57.9–94.1), efficacy against severe RSV-related lower respiratory tract disease was 94.1% (95% CI, 62.4–99.9) and against RSV-related acute respiratory infection was 71.7% (95% CI, 56.2–82.3)⁵.

This discovery opened a new avenue towards the management and cure of RSV worldwide. Unfortunately, the given trial was conducted only on the adult population⁵. It is here important to acknowledge the exclusion of infants in the trial sample despite the substantial burden of RSV infections they face, particularly in low- and middle-income countries (LMIC)⁶. In LMIC, severe RSV lower respiratory tract involvement (LRTI) causes annual 1.0 million hospital admissions, while very severe LRTI causes 0.6 million, especially in infants less than six months of age⁶. RSV is one of the top causes of mortality in the pediatric population, accounting for 59 600 fatalities in children under the age of five each year⁷. A humanized monoclonal antibody against the RSV fusion glycoprotein called Palivizumab was given FDA approval in 1998 to prevent severe RSV infections in susceptible infants⁸. However, Palivizumab prophylaxis only reduces hospitalization for RSV infection and has little to no effect on controlling mortality or morbidity⁹. Unlike Palivizumab, the RSVpreF vaccine prevents RSV-related respiratory infections, severe lower respiratory tract diseases, and death. Its RSVpreF antigen prompts a tenfold increase in neutralizing antibodies^4,5. Additionally, a phase 2B trial reported the occurrence of no serious adverse effects, with a significant rise in neutralizing titer and CD4+ T cell frequency among the participants after the third dose¹⁰.

RSV poses a substantial threat to global infant health, and current treatment options for RSV-associated LTRI are limited¹¹. The introduction of an FDA-approved RSV vaccine for adults provides an encouraging opportunity for the development and implementation of RSV vaccines specifically designed for infants. In the past, LMICs like Ethiopia utilized WHO’s country-led Assessment for Prioritization on Immunization (CAPACITI) tool for vaccination prioritization. At the same time, Zambia employed community health workers for vaccine distribution in their regions^12,13. LMICs can make use of such targeted strategies, such as the inclusion of RSV vaccination in the national immunization programs on a priority basis, using community health workers to approach parents of young infants on the grassroots level to advocate for the vaccine on a one-to-one basis^12,13. We can particularly encourage doctors in primary healthcare settings to introduce the RSV vaccines to the parents of young infants in these remote areas and counsel them regarding the dreadful health and financial outcome of the disease^12,13. LMICs should adopt such targeted strategies to aid in the adequate dispersal of the RSV vaccine among infants^12,13.

Filling the RSV prevention gap in infants promises reduced mortality, less morbidity, optimized resource use, and cost savings. In conclusion, it’s time to conduct RSV vaccine trials in infants, paving the way for future vaccination programs to protect them from RSV. However, it is crucial to ensure ethical considerations while conducting trials on infants. For this, we believe that any such trial in the future must be conducted only after obtaining informed consent from parents and approval from the ethics committee. The trial should be designed to minimize any risks to the infants. This includes using the smallest possible effective dose, monitoring for adverse effects closely, and having protocols in place to address any adverse events quickly. Also, ensure potential benefits justify risks, maintain transparency, provide post-trial access to rigorous monitoring, offer alternative treatments, and include pediatric experts to safeguard infant welfare and advance scientific knowledge. By adhering to these ethical guidelines, the trial can be conducted in a manner that respects the rights and welfare of the infant participants while advancing important scientific knowledge about RSV vaccines.

Future research

Future research in the field of RSV should focus on the following areas to address the gaps and challenges highlighted in this article and to conduct Clinical Trials in Infants to ensure comprehensive protection against RSV. The trial should minimize infant risks by using the smallest effective dose, closely monitoring for adverse effects, and having protocols to address issues quickly. These trials should evaluate the safety, efficacy, and immunogenicity of RSV vaccines in this vulnerable population, taking into account different age groups and geographical regions.

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The authors have not received any funds.

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All authors have equally contributed to the manuscript and have approved the final manuscript to be published.

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The authors declare that they have no financial conflict of interest with regard to the content of this report.

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