Immunization technologies: Time to consider new preventative solutions for respiratory syncytial virus infections

ABSTRACT

New technologies for the prevention of infectious diseases are emerging to address unmet medical needs, in particular, the use of long-acting monoclonal antibodies (mAb) to prevent Respiratory Syncytial Virus (RSV) lower respiratory tract disease in infants during their first RSV season. The lack of precedent for mAbs for broad population protection creates challenges in the assessment of upcoming prophylactic long-acting mAbs for RSV, with associated consequences in legislative and registration categorization, as well as in recommendation, funding, and implementation pathways. We suggest that the legislative and regulatory categorization of preventative solutions should be decided by the effect of the product in terms of its impact on the population and health-care systems rather than by the technology used or its mechanism of action. Immunization can be passive and active, both having the same objective of prevention of infectious diseases. Long-acting prophylactic mAbs work as passive immunization, as such, their recommendations for use should fall under the remit of National Immunization Technical Advisory Groups or other relevant recommending bodies for inclusion into National Immunization Programs. Current regulations, policy, and legislative frameworks need to evolve to embrace such innovative preventative technologies and acknowledge them as one of key immunization and public health tools.

KEYWORDS:

• Infant immunization
• long-acting monoclonal antibody
• passive immunization
• prophylactic monoclonal antibody
• respiratory syncytial virus

Introduction

An increasing amount of innovative preventative interventions has emerged recently, including monoclonal antibodies (mAbs) and other antigen-binding proteins based on immunoglobulin scaffolds.^1–3 There is now an expanded scope of licensed uses for preventative mAbs^2–4 with an active pipeline of more than 20 clinical trials ongoing against a broad range of antigens covering human immunodeficiency virus (HIV), malaria, Ebola, and respiratory syncytial virus (RSV),⁵ providing innovative immunization tools demonstrating the potential to address unmet medical needs in a range of populations.

New immunization opportunities are becoming available to reduce the burden of RSV, with both maternal vaccines and long-acting mAbs which could provide passive immunization for the prevention of RSV lower respiratory tract diseases (LRTD) in a broad infant population.⁶ However, despite evidence of efficacy and safety as well as strong commonalities with conventional vaccines in terms of administration and public health benefit (Table 1), long-acting RSV mAbs face challenges as for their appropriate classification in registration categories to access immunization channels and their inclusion into immunization recommendation, funding, and implementation frameworks.^7–9

Table 1. Commonalities between vaccines and long-acting preventative mAbs.

Category	Commonalities shared between vaccines and long-acting preventative mAbs
Ultimate purpose	Prevention of infectious diseases among broad populations
Target population	Intended for use in a broad population, designed to protect throughout the period of highest risk
Administration	Administered routinely in primary care, general clinics, and/or in hospitals
Presentation & Delivery	Classic vaccine distribution and administration channels
Evidence	Followed for safety and efficacy at the population level
Pathway	Adoption and uptake driven by recommendations from national and supra-national immunization advisory groups

The wider therapeutic use of mAbs and their relatively limited prophylactic use in clinical practice has led to substantial misconceptions related to the use of preventative mAbs in broad populations.^10,11 This mismatch between emerging evidence and existing policy frameworks could limit the availability and access of preventative mAbs to broader recipients and miss out on the potential benefits offered by these new preventative solutions. There needs to be a reflection on how to recognize them as immunization opportunities in prevention and to facilitate their broad access.

Methods

These findings are based on insights shared by nine global experts (China, France, Germany, Italy, Japan, Spain, and the United Kingdom) during an advisory board meeting held in July 2022 to discuss perspectives on an all-infant RSV immunization program with a mAb. Further materials used to support the writing of this commentary include results of clinical trials and additional scientific desk research, including scholarly publications and official reports.

Discussion

Reflection on the concept of immunization

Immunization is the process whereby a person is made immune or resistant to an infectious disease. Although usually considered synonymous with vaccination or inoculation, immunization is usually considered active or passive, two processes that, though differing in their mechanism of action, ultimately serve the same purpose – namely, protection against infectious disease.^12,13

Active immunization is the most common form of immunization, whereby the host’s immune response is elicited through the interaction of the immune system with a pathogen/antigen or by the administration of a vaccine. Passive immunization, conversely, embraces a variety of tools such as maternal vaccines or mAbs and other immunoglobulins. Maternal vaccines generate passive immunization through the natural transfer of maternal antibodies from placenta to fetus, providing transient and waning protection during the first weeks to months of life.^14–16 mAbs are synthetic neutralizing antibodies designed to act directly and specifically on a certain part of a pathogen, acting like an antibody and providing passive immunization.^3,4,17

Passive immunization toward certain pathogens has been beneficial in clinical settings for decades, and recent improvements have led to a growing potential for expanded use.^18,19 For instance, immunoglobulins are used as post-exposure prophylaxis for infections, including tetanus and hepatitis B virus.^20,21 During the early stages of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, convalescent plasma (i.e. polyclonal antibodies) was employed as a seemingly promising option for improving the recovery of severe cases.^22,23

In the field of RSV, several immunization solutions for broad population protection are being considered, comprising both active and passive immunization options:

• A novel long-acting mAb, Nirsevimab, approved by the European Medicines Agency (EMA) and the United Kingdom (UK) Medicines and Healthcare products Regulatory Agency (MHRA) for the prevention of RSV LRTD in newborn babies and infants during their first RSV season.^7,24 Nirsevimab was designed to be administered at birth to infants born during the RSV season or at the season’s start for infants born prior to the season. Single-dose immunization is expected to cover a typical RSV season for at least 5 months in temperate countries.

• A maternal vaccine candidate under development may have potential to address unmet medical needs as well;²⁵ however, the protection of the infant may be more limited in extreme prematurity when the infant may not receive the full benefit of antibody transfer²⁶ and for infants born prior to the RSV season. Moreover, the timing of immunization during the pregnancy is key to achieve the highest benefit for the newborn.

• In addition, RSV pediatric vaccine candidates which generate active immunization are currently in development, some of which are designed to provide protection for infants and children in subsequent RSV seasons after the first one.²⁷

Considerations for introducing long-acting mAbs in National Immunization Programs

Due to the lack of precedent for the use of mAbs for prevention of infectious disease in broad populations, prophylactic long-acting mAbs may not fit with the current legislative and regulatory immunization framework of some countries, potentially impeding their inclusion in National immunization Programs (NIP).⁴ However, passive immunization from mAbs would have a similar impact on public health as active immunization from vaccines, especially given the rapid, direct, and timely protection that can be delivered in a large population.^2–4

The effect of prophylaxis in terms of its impact on health-care systems and wider populations is more important than the technology used or its mechanism of action.²⁸ Recommendations for using prophylactic mAbs should fall under the remit of the National Immunization Technical Advisory Groups (NITAGs) or other relevant recommending bodies for inclusion into NIPs.

Since 2018, the European Centre for Disease Prevention and Control (ECDC) has recommended that the collaboration between NITAGs in the European Union and the European Economic Area should include pathogen-specific immunoglobulins or mAbs when relevant.²⁹ In March 2022, the United States NITAG (Advisory Committee on Immunization Practices (ACIP)) updated its charter, outlining an official path forward for ACIP to review monoclonal antibodies for disease prevention.³⁰ The UK NITAG Joint Committee on Vaccination and Immunisation (JCVI) has also specified “the provision of vaccination and immunization services being facilities for the prevention of illness.”¹²

However, in some countries, existing regulations and legislative frameworks still need to evolve to embrace new prophylactic options, such as long-acting mAbs, and to allow broad and equitable access to all available preventative tools, whatever their mechanism of action, through routine immunization programs.

Case study: implications for RSV prevention in infants

RSV is a common cause of LRTDs in newborns and infants.³¹ Worldwide, approximately 33.1 million RSV infections occur annually in children less than 5 years of age.³² RSV is one of the leading causes of hospitalization among infants under 1 year of age with more than 70% of hospitalizations for RSV occurring in healthy infants born at term.^33,34 For example, in France, the RSV epidemic season 2022–23, following the lift of COVID-19 nonpharmacologic measures, was the highest observed in a decade, leading to a large number of hospitalizations due to bronchiolitis, and saturating capacity in pediatric wards.³⁵

To date, RSV remains one of the childhood diseases where no effective vaccine or immunization options are available for a broad population.^31,36 Despite more than 60 years of research into RSV prevention, most vaccine development attempts have failed during clinical trials, although maternal vaccine candidates have entered late clinical development.^37–39 Until 2022, the only licensed monoclonal antibody recommended for the prevention of severe RSV infections (palivizumab) is recommended for a restricted population and requires monthly injection, i.e. five doses for coverage across a typical RSV season in a temperate climate.^40–42 In November 2022, a long-acting mAb, nirsevimab (Beyfortus®), was approved by the EMA and the MHRA⁴³ for the prevention of RSV LRTD in neonates and infants during their first RSV season, addressing an unmet public health need.

Nirsevimab has demonstrated efficacy in healthy term and preterm infants of at least 5 months with some follow-up studies showing antibody persistence up to 365 days, and clinical trials have shown a marked reduction in medically attended RSV-associated LRTD⁷ and hospitalizations. Through its more convenient single-dose approach,⁴⁴ this long-acting mAb has the potential to protect a broad infant population against RSV.

Despite its clinically proven acceptable safety profile and efficacy endpoints, uncertainty remains on whether this preventative long-acting mAb will be recognized and evaluated as an immunization, with associated consequences in terms of registration, recommendation, funding, and implementation, with delays in availability and access. For example, legal barriers in some countries may place the use of preventative mAbs entirely out of the scope of NITAG assessment; and, in some countries, NIP implementation as well as the relevant funding schemes are limited to vaccines, excluding prophylactic long-acting mAbs.

The need to prepare for RSV mAb licensure and to identify and address gaps in the pathway to policy recommendation and implementation has been highlighted.^45,46 To secure access to preventative mAbs for a broad population, revised pathways for this new prophylactic solution are needed, as can already be seen in certain countries like the US and UK. In some countries, such as France, Italy, and Spain, scientific societies have published guidelines on the use of the prophylactic long-acting RSV mAb, targeting all infants during their first year of life to be protected.^47–49

To modernize the immunization framework and enable mAbs to be used as prophylaxis for a broad population, there is a need for preventative long-acting mAbs to be:

• Considered for use in a general (infant) population according to product indication (subject to cost-effectiveness).

• Categorized as prophylactic immunizations from a regulatory category and legal standpoint.

• Assessed by the NITAG or other relevant recommending bodies as is the case for other childhood or maternal vaccines.

• Considered as eligible in each country for possible inclusion in the NIP and thus in national vaccine funding.

• Prepared from both clinical practice and programmatic perspectives for implementation in national immunization programs.

Conclusion

Although the use of long-acting mAbs as prophylactics for a broad population can challenge existing categorization schemes, especially when there is no precedent, immunization programs should encompass these new preventative solutions which share the same ultimate goals and play the same public health roles as active vaccines.

Preventative RSV long-acting mAbs, to be used for broad populations, can provide an opportunity for longstanding and innovative immunization solutions. Current national regulations and legislative frameworks may need to change in some countries for new prevention solutions and thereby provide equitable access for all infants. To prepare for the implementation of this new type of immunization program, NITAGs or other assessment bodies play a central role in achieving more equitable health care and allowing population access to innovative preventative tools.

Author contributions

All authors critically reviewed and approved the manuscript. All authors are accountable for the accuracy and integrity of the manuscript.

Acknowledgments

The authors acknowledge Dr Matteo Riccò (Department of Public Health, ASL Reggio Emilia, Italy), for providing editorial assistance with the preparation of this manuscript. The manuscript preparation received support from Flora Leadley, Thierry Rigoine de Fougerolles and Olivier Vitoux (CVA, Paris, France). Andrew Lane (Lane Medical Writing, France) provided additional editorial support.

Disclosure statement

Catherine Weil-Olivier declares grants or contracts and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events with Astra Zeneca, GSK, Janssen, Medimmune, Pfizer, Sanofi, and Sanofi-Aventis; Consulting fees as punctual consultant or directly as independent expert with Astra Zeneca, GSK, Janssen, Medimmune, MSD, Pfizer, Sanofi, and Sanofi-Aventis; Leadership or fiduciary role in Coalition for Life Course Immunisation and Infovac-France. David Salisbury declares consulting fees with BioNTech, GSK, J&J, Moderna, Pfizer, Sanofi, and Seqirus; Stock options with Clover Pharmaceuticals. José Antonio Navarro Alonso declares payment or honoraria for lectures and support for attending meetings and/or travel with Astra Zeneca, GSK, MSD, Sanofi, and Seqirus. Chryssoula Tzialla declares payment or honoraria after authorization from their institution for events sponsored by Astra Zeneca and Sanofi. Yan Zhang has nothing to disclose. Susanna Esposito declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events with Moderna, MSD, Pfizer, Sanofi, and Vifor; Support for attending meetings and/or travel with Moderna, MSD, Novavax, Pfizer, Sanofi, and Vifor; Participation on a Data Safety Monitoring Board or Advisory Board with Janssen, Moderna, MSD, Novavax, Pfizer, Qiagen, Sanofi, and Vifor. Fabio Midulla has nothing to disclose. Tobias Tenenbaum declares payment or honoraria for lectures with Astra Zeneca, Diasorin, GSK, MSD, and Sanofi; Non-financial interests.

Additional information

Funding

The work was supported by the Sanofi Pasteur. Sanofi supported the organization of the RSV Experts Group Event, where the decision to submit for publication was made. Authors were not paid for writing the publication, while remuneration to the experts was agreed for the time spent for the meeting. CVA received funding from Sanofi to support the expert meeting organization, medical writing, and editorial support.