The journey to a respiratory syncytial virus vaccine

doi:10.1016/j.anai.2020.03.017

Annals of Allergy, Asthma & Immunology

Volume 125, Issue 1, July 2020, Pages 36-46

https://doi.org/10.1016/j.anai.2020.03.017 Get rights and content

Abstract

Objective

The high burden associated with respiratory syncytial virus (RSV) has made the development of RSV vaccine(s) a global health high priority. This review summarizes the journey to an RSV vaccine, the different strategies and challenges associated with the development of preventive strategies for RSV, and the diverse products that are undergoing clinical testing.

Data Sources

Studies on RSV biology, immunology, epidemiology, and monoclonal antibodies (mAbs) and vaccines were searched using MEDLINE. We also searched PATH.org and ClinicalTrials.gov for updated information regarding the status of RSV vaccines and mAbs undergoing clinical trials.

Study Selections

We selected relevant studies conducted in infants and young children, pregnant women, and elderly population for the prevention of RSV infection.

Results

Identification of a safe and immunogenic vaccine has been an important but elusive initiative for more than 60 years for different reasons, including the legacy of formalin-inactivated vaccine, our limited understanding of the immune response to RSV and how it relates to clinical disease severity, or the need for different end points according to the different vaccine platforms. Nevertheless, there are currently 39 vaccines and mAbs under development and 19 undergoing clinical trials.

Conclusion

Over the past decade, there have been significant advances in our knowledge of RSV molecular and structural biology and in understanding the human immune response to RSV. Despite the barriers, there are several promising mAbs and RSV vaccines undergoing clinical trials that hope to offer protection to the most vulnerable populations.

Introduction

Respiratory syncytial virus (RSV) is one of the great threats to child health and is associated with considerable short-term and long-term morbidity.1, 2, 3, 4 In infants and toddlers, RSV is the leading cause of viral lower respiratory tract infection (LRTI, including bronchiolitis and pneumonia) worldwide. Globally, it is estimated that RSV causes 33 new million episodes of acute LRTI in children younger than 5 years, resulting in approximately 3.2 million hospitalizations per year and approximately 120,000 deaths annually.⁵ In resource-limited countries, RSV represents the second most common cause of infant mortality.⁶

In adults, the few studies published to date suggest that RSV carries a significant burden, especially in elderly where it is associated with substantial morbidity and mortality. In this patient population, RSV is responsible for approximately 1.5 million episodes of LRTI and mortality rates that range from 4% to 10%, depending on the patient characteristics, with those with underlying cardiac or pulmonary diseases carrying the highest mortality rates.7, 8, 9, 10, 11, 12 In addition, RSV is a major pathogen for immunocompromised individuals¹³ and has been associated with the development of persistent wheezing and asthma.¹⁴^,¹⁵

Respiratory syncytial virus is ubiquitous, with relatively homogeneous distribution worldwide, and invariably and predictively causes yearly outbreaks. By their first birthday, nearly 70% of infants have been infected with RSV at least once, and essentially all children are infected with this virus within the first 2 years of life.¹⁶ The increasingly recognized burden associated with RSV has made the development of RSV vaccine(s) a global health high priority. The World Health Organization has developed a research and development roadmap to facilitate the development and implementation of vaccines and monoclonal antibodies (mAbs) in low- and middle-income countries and estimates that RSV vaccination will be available in the next 5 to 10 years.¹⁷ This review summarizes the history and journey of RSV vaccines, the different strategies and challenges associated with the development of RSV vaccines and mAbs, and the diverse products that are undergoing clinical testing.

Section snippets

RSV Structure

Respiratory syncytial virus is an orthopneumovirus that belongs to the recently created Pneumoviridiae family. Human RSV exists as 2 antigenic subgroups, A and B, which can cocirculate during the same season and exhibit genome-wide sequence divergence. The nonsegmented, single-stranded, negative-sense genome contains 10 genes (15,222 nucleotides) that encode 11 proteins. Of those, 3 are nonstructural proteins (NS1, NS2, and M2-2), and 8 are structural proteins (Fig 1).

Of the 8 structural

Challenges Associated With the Development of RSV Vaccines

In 1956, a new cytopathogenic virus, chimpanzee coryza virus, was identified. However, a serosurvey found antibodies to this virus in humans, not chimpanzees.³¹ What later came to be known as RSV was first isolated from infants with severe lower respiratory tract illness by Robert Chanock in 1957.³² The infant disease burden associated with RSV has been recognized for many years; however, identification of a safe and immunogenic vaccine has been an important but elusive goal for more than 60

Clinical End Points

The main goal of an RSV vaccine is a reduction of disease severity; however, the lack of a standard definition of severe disease and/or precise markers to assess clinical disease severity in infants has represented for years an important barrier for vaccine development. This problem is related to our limited understanding of the immune response to RSV and how it relates to clinical disease severity.53, 54, 55, 56, 57, 58

Clinical end points that define a successful vaccine might be different,

Immune Correlates of Protection

Defining the immune correlates of protection for RSV vaccines requires a better understanding of disease pathogenesis, immunity, and transmission dynamics. Achieving sterilizing immunity, although attractive, might not be possible or even desirable because RSV reexposures in the upper airway may be sufficient to boost the immune response, limiting progression of the infection to the lower respiratory tract and/or RSV transmission. Serum neutralizing antibodies (IgG against pre-F, post-F, and G)

Vaccine Strategies

In recent years, there has been an explosion of passive and active immunization strategies for RSV moving through the drug discovery pipeline.⁶⁷ Different vaccine strategies are being explored for preventing severe RSV infection in the main target populations: protein vaccines that use stabilized pre-F protein subunits or viruslike particles, live vaccines that included attenuated RSV strains, or virus vectors that express RSV proteins. Age and whether patients are naive (or have been

mAbs

mAbs are also being evaluated for the prevention of RSV LRTI in young infants (Fig 2).⁷¹ They have advanced faster and more successfully than RSV vaccines because of their enhanced efficacy while potentially improving patient adherence because fewer doses will be required and ultimately reducing costs. However, there is the possibility of developing escape mutations that may alter the susceptibility of natural RSV strains that lack the epitope for the mAb. This possibility emphasizes the need

Conclusion

During the past decade, there have been significant advances in our knowledge of RSV molecular and structural biology and in the understanding of the human immune response to RSV. In addition, the increasing interest of academic, industry, and international entities, such as the World Health Organization and the Bill & Melinda Gates Foundation, is helping to rapidly move this field forward, promoting the implementation of surveillance platforms and standardization of clinical definitions,

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Current situation of intranasal attenuated vaccines against respiratory syncytial virus in the child population
2024, Vacunas
El virus respiratorio sincitial (VRS) es el causante de las enfermedades respiratorias agudas (bronquiolitis y neumonías) que se presentan preferentemente en la población infantil de forma epidémica. La única forma de prevenir estas infecciones es mediante la vacunación previa de los mayores de 6 meses. De las diferentes vacunas existentes, las vacunas atenuadas, definidas como aquellas que contienen un virus alterado o modificado para disminuir al máximo su capacidad patogénica, pero manteniendo su capacidad de respuesta inmunológica, parecen representar un importante avance. En los últimos años se han evaluado 2 candidatas vacunales basadas en la deleción del gen M2-2, las designadas como MEDI/ΔM2 y la LID/ΔM2-2/1030s. En el estudio realizado en 21 niños seronegativos (6-24 meses), estos recibieron una dosis intranasal (10⁵ PFU) de la nueva vacuna frente a un grupo placebo. El 85% de los vacunados desarrollaron un título de anticuerpos neutralizantes 4 veces mayor al previo. La combinación de la deleción Δ1313 con la deleción de la NS2 se mostró mejor para la elaboración de un candidato vacunal recombinante atenuado del VRS (ΔNS2/Δ1313), con buenos resultados protectores. Se desarrolló un nuevo candidato vacunal designado como RSV/6120/ΔNS2/1030s que es idéntico al virus previo RSV/ΔNS2/Δ1313/I1314L, pero con mutaciones adicionales. Finalmente se ha desarrollado un VRS de un solo ciclo replicativo eliminando el gen codificador de la proteína de matriz (M) (VRS-M-null). La mayoría de estas vacunas están todavía en fase 2/3 y se esperan muy buenos resultados.
The respiratory syncytial virus (RSV) is the cause of acute respiratory pathologies (bronchiolitis and pneumonia), which occur preferably in the pediatric population in an epidemic manner. The only way to prevent these infections is through prior vaccination of children older than 6 months. Of the different existing vaccines, attenuated vaccines, defined as those that contain an altered or modified virus to minimize its pathogenic capacity while maintaining its immunological response capacity, seem to represent an important advance. In recent years, two vaccine candidates based on the M2-2 gene deletion have been evaluated, those designated MEDI/ΔM2 and LID/ΔM2-2/1030s. In the study carried out in 21 seronegative children (6-24 months), they received an intranasal dose (10⁵ PFU) of the new vaccine compared to a placebo group. Eighty-five percent of those vaccinated developed a neutralizing antibody titer 4 times greater than the previous one. The combination of the Δ1313 deletion with the NS2 deletion was shown to be better for the development of an attenuated RSV recombinant vaccine candidate (ΔNS2/Δ1313), with good protective results. A new vaccine candidate designated RSV/6120/ΔNS2/1030s was developed that is identical to the previous virus RSV/ΔNS2/Δ1313/I1314L but with additional mutations. Finally, a RSV with a single replicative cycle has been developed by eliminating the gene encoding the matrix (M) protein (RSV-M-null). Most of these vaccines are still in phase 2/3 and very good results are expected.
Two synthetic steroid analogs reduce human respiratory syncytial virus replication and the immune response to infection both in vitro and in vivo
2023, Heliyon
HRSV is responsible for many acute lower airway infections and hospitalizations in infants, the elderly and those with weakened immune systems around the world. The strong inflammatory response that mediates viral clearance contributes to pathogenesis, and is positively correlated with disease severity. There is no specific effective therapy on hand. Antiviral synthetic stigmastanes (22S, 23S)-22,23-dihydroxystigmast-4-en-3-one (Compound 1) and 22,23-dihydroxystigmasta-1,4-dien-3-one (Compound 2) have shown to be active inhibiting unrelated virus like Herpes Simplex type 1 virus (HSV-1) and Adenovirus, without cytotoxicity. We have also shown that Compound 1 modulates the activation of cell signaling pathways and cytokine secretion in infected epithelial cells as well as in inflammatory cells activated by nonviral stimuli. In the present work, we investigated the inhibitory effect of both compounds on HRSV replication and their modulatory effect on infected epithelial and inflammatory cells. We show that compounds 1 and 2 inhibit in vitro HRSV replication and propagation and reduce cytokine secretion triggered by HRSV infection in epithelial and inflammatory cells. The compounds reduce viral loads and inflammatory infiltration in the lungs of mice infected with HRSV.
Current situation and future perspectives of vaccines against respiratory syncytial virus
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El virus respiratorio sincitial (VRS) es el causante de enfermedades respiratorias agudas (bronquiolitis y neumonías) que se presenta preferentemente de forma epidémica en los meses invernales. El VRS es un buen candidato vacunal, ya que como virus ha mostrado una estabilidad genética y antigénica, la mayoría de las infecciones son autolimitadas y el único reservorio natural es el ser humano. De acuerdo con los datos epidemiológicos existen 3 poblaciones diana que requieren de aproximaciones diferentes para la vacuna frente al VRS: los niños naive < 4-6 meses, los niños > 6 meses y los > 65 años. En estos momentos se están estudiando múltiples plataformas vacunales, basadas en la proteína preF, aunque hay que considerar la utilización de los anticuerpos monoclonales de vida prolongada en el primer año de vida. En la población infantil, más allá de este período, probablemente las vacunas atenuadas tengan un papel relevante, ya que exponen al sistema inmune la partícula vírica completa e inducen una respuesta de anticuerpos neutralizantes de amplio espectro. En la población de > 65 años, es evidente la necesidad de utilizar una vacuna de subunidades con un adyuvante que estimule la respuesta inmune o las vacunas de ARNm. El futuro en la prevención de la infección y enfermedad por VRS en la población humana, se basará en la utilización de anticuerpos monoclonales y vacunadas adaptadas a cada grupo de edad.
The respiratory syncytial virus (RSV) is the cause of acute respiratory pathologies (bronchiolitis and pneumonia) that occurs preferably as epidemic in the winter months. RSV is a good vaccine candidate since as a virus it has shown genetic and antigenic stability, most infections are self-limited and the only natural reservoir is humans. According to epidemiological data, there are three target populations that require different approaches for the RSV vaccine: naive children < 4-6 months, children > 6 months, and > 65 years. Multiple vaccine platforms based on the preF protein are currently being studied, although the use of long-lived monoclonal antibodies must be considered in the first year of life. In the child population, beyond this period, attenuated vaccines probably play a relevant role, since they expose the complete viral particle to the immune system and induce a broad-spectrum neutralizing antibody response. In the population > 65 years of age, the need to use a subunit vaccine with an adjuvant that stimulates the immune response or mRNA vaccines is evident. The future in the prevention of RSV infection and disease in the human population will be based on the use of monoclonal antibodies and vaccines adapted to each age group.
Current strategies and perspectives for active and passive immunization against Respiratory Syncytial Virus in childhood
2023, Jornal de Pediatria
Citation Excerpt :
Currently, there are 17 vaccines and three monoclonal antibodies in ongoing or completed clinical trials, as shown in Table 1. Figure 1 summarizes the overview of the main vaccine groups in all preclinical and clinical studies for the different target populations.14–16,22 Extensive epidemiological evidence highlights the potential of maternal vaccination to protect infants from diseases such as pertussis, influenza, and COVID-19.24
Despite the global impact of the Respiratory Syncytial Virus (RSV) infection in children, only one monoclonal antibody (Palivizumab) has been approved for clinical use. However, advances in the knowledge of RSV immunology may enable the development of safe and effective new vaccines and monoclonal antibodies in a few years. The purpose of this review is to summarize available data on approved and developing passive and active immunizations against RSV in childhood and pregnancy.
A non-systematic review of RSV immunoprophylaxis in childhood and pregnancy was carried out in PubMed, path.org and clinical trial registries, without language restrictions, up to September 2022.
Three monoclonal antibodies and 17 active immunization candidates are under development in phase 1 to 3 clinical studies. Regarding the first group, Nirsevimab is a monoclonal antibody with a prolonged half-life whose approval for clinical use is expected in the next months. Among the vaccines under development, six techniques are being used: protein subunit, viral particles, live attenuated virus, recombinant viral vector, chimeric, and mRNA. The first two approaches are being tested primarily in pregnancy, while the others are being developed for the pediatric population.
The approval of extended half-life monoclonal antibodies is the next expected advance in RSV prevention, although the costs may be a barrier to the implementation. Regarding active immunizations, maternal and infant vaccination are complementary strategies and there are many promising candidates in clinical studies using different platforms.
Laser-assisted intradermal delivery of a microparticle vaccine for respiratory syncytial virus induces a robust immune response
2023, Vaccine
Respiratory syncytial virus (RSV) is an infectious disease that poses a significant public health risk in young children. Vaccine studies conducted in the 1960s using an intramuscular injection of formalin-inactivated respiratory syncytial virus (Fi-RSV) resulted in an enhanced respiratory disease and led to the failure of the vaccine. Thus, the virus-like particles (VLP) of the RSV fusion (F) protein was used as the vaccine antigen in this study. The F-VLP was encapsulated in a microparticle (MP) matrix composed of cross-linked bovine serum albumin (BSA) to enhance the antigen presentation and uptake. Moreover, a painless vaccination method would be desirable for an infectious disease that mainly affects young children. Thus, an ablative laser device, Precise Laser Epidermal System (P.L.E.A.S.E), was utilized to create micropores on the skin for vaccine delivery. We observed enhanced antigen presentation of the vaccine microparticles (F-VLP MP) with and without the adjuvant monophosphoryl lipid A (MPL-A) MP in dendritic cells. Consequently, Swiss Webster mice were immunized with the adjuvanted vaccine microparticles using the P.L.E.A.S.E laser to study the in vivo immunogenicity. The immunized mice had high serum immunoglobulin (IgG, IgG2a) levels, indicating a Th1 response. Subsequent analysis of lung homogenates post- RSV challenge revealed high IgA, indicating generation of a mucosal immune response upon intradermal immunization. Flowcytometry analysis showed high CD8+, and CD4+ expression in the lymph node and spleen of the adjuvanted vaccine microparticle immunized mice. Increased expression of interferon gamma (IFN-γ) in the spleen cells further proved Th1 polarized immune response. Finally, an immune plaque assay indicated significantly low lung viral titer in the mice immunized with intradermal adjuvanted vaccine microparticles. Thus, ablative laser-assisted immunization with the F-VLP based adjuvanted vaccine microparticles could be a promising vaccine candidate for RSV.
Verapamil Inhibits Respiratory Syncytial Virus Infection by Regulating Ca2+ Influx
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: Disclosures: Dr Mejias has received fees for participation in advisory boards from Janssen and Roche. Dr Rodríguez-Fernández has received fees for participation in advisory boards and lectures from AbbVie. Dr Peeples has received fees for participation in an advisory board from ReViral and lectures from Pfizer. Dr Ramilo has received fees for participation in advisory boards from Merck, MedImmune/Sanofi Pasteur, and Pfizer and fees for lectures from Pfizer.

: Funding Sources: This study was supported by National Institutes of Health/National Institute of Allergy and Infectious Diseases (research grant AI112524 from the) to Drs Mejias, Peeples, and Ramilo and research grant FIS PI16/00822 from the Fondo de Investigacion Sanitarias, Instituto de Investigación Sanitaria Gregorio Marañón (Dr Rodríguez-Fernández).

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ReviewThe journey to a respiratory syncytial virus vaccine

Abstract

Objective

Data Sources

Study Selections

Results

Conclusion

Introduction

Section snippets

RSV Structure

Challenges Associated With the Development of RSV Vaccines

Clinical End Points

Immune Correlates of Protection

Vaccine Strategies

mAbs

Conclusion

Lancet

Lancet

Lancet

Lancet

Vaccine

Virology

Microbes Infect

Virology

Curr Opin Virol

Vaccine

Curr Opin Immunol

Vaccine

Immunity

Vaccine

J Pediatr

Lancet Infect Dis

Vaccine

Risk factors in children hospitalized with RSV bronchiolitis versus non-RSV bronchiolitis

Pediatrics

The burden of respiratory syncytial virus infection in young children

N Engl J Med

Bronchiolitis-associated hospitalizations among US children, 1980-1996

JAMA

Respiratory syncytial virus infection in elderly and high-risk adults

N Engl J Med

Respiratory syncytial virus and influenza A infections in the hospitalized elderly

J Infect Dis

Acute viral infections of upper respiratory tract in elderly people living in the community: comparative, prospective, population based study of disease burden

BMJ

Epidemiology and outcomes of hospitalized adults with respiratory syncytial virus: a 6-year retrospective study

Influenza Other Respir Viruses

Respiratory syncytial virus infection-associated hospitalization in adults: a retrospective cohort study

BMC Infect Dis

Respiratory virus pneumonia after hematopoietic cell transplantation (HCT): associations between viral load in bronchoalveolar lavage samples, viral RNA detection in serum samples, and clinical outcomes of HCT

J Infect Dis

Risk of childhood wheeze and asthma after respiratory syncytial virus infection in full-term infants

Pediatr Allergy Immunol

Risk of primary infection and reinfection with respiratory syncytial virus

Am J Dis Child

Lung surfactant protein A provides a route of entry for respiratory syncytial virus into host cells

Viral Immunol

CX3C chemokine mimicry by respiratory syncytial virus G glycoprotein

Nat Immunol

Respiratory syncytial virus infection of human airway epithelial cells is polarized, specific to ciliated cells, and without obvious cytopathology

J Virol

Respiratory syncytial virus matures at the apical surfaces of polarized epithelial cells

J Virol

Human CD8(+) T cell responses against five newly identified respiratory syncytial virus-derived epitopes

J Gen Virol

Respiratory syncytial virus uses CX3CR1 as a receptor on primary human airway epithelial cultures

PLoS Pathog

Structure of respiratory syncytial virus fusion glycoprotein in the postfusion conformation reveals preservation of neutralizing epitopes

J Virol

Recovery of cytopathogenic agent from chimpanzees with coryza

Proc Soc Exp Biol Med

Recovery of a new type of myxovirus from infants with croup

Ann N Y Acad Sci

Immunity to and frequency of reinfection with respiratory syncytial virus

J Infect Dis

Synergistic induction of interferon α through TLR-3 and TLR-9 agonists identifies CD21 as interferon α receptor for the B cell response

PLoS Pathog

Field evaluation of a respiratory syncytial virus vaccine and a trivalent parainfluenza virus vaccine in a pediatric population

Am J Epidemiol

Pre-fusion F is absent on the surface of formalin-inactivated respiratory syncytial virus

Review
The journey to a respiratory syncytial virus vaccine