Respiratory Syncytial Virus Vaccines

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This entry is adapted from the peer-reviewed paper 10.3390/vaccines8040672

Respiratory Syncytial Virus (RSV) is the main cause of acute respiratory tract infections in infants and it also induces significant disease in the elderly, with a potentially severe clinical course and a large number of deaths in developing countries and of intensive care hospitalizations worldwide. To date, prevention strategies against RSV infection are based on hygienic measures and passive immunization with humanized monoclonal antibodies limited to selected high-risk children due to their high costs. The development of a safe and effective vaccine is a global health need and an important objective of research in this field. A growing number of RSV vaccine candidates in different formats (particle-based vaccines, vector-based vaccines, subunit vaccines, and live-attenuated vaccines) are being developed and are now at different stages. While waiting for commercially available safe and effective vaccines, immune prophylaxis in selected groups of high-risk populations is still mandatory.

RSV vaccine prevention

1. Epidemiology

Respiratory syncytial virus (RSV) is often responsible for severe seasonal respiratory disease in infants and elderly people, and it causes a great burden on health systems worldwide. RSV clinical presentation in children involves respiratory infections ranging from mild upper to severe lower respiratory tract infections (LRTI), including pneumonia or bronchiolitis ^[1]^[2]^[3]^[4]; in fact, it was estimated that RSV may cause up to 22% of all severe acute LRTI in young children. A recent systematic review ^[3] reported that worldwide in 2015, RSV caused 33.1 million episodes of LRTI, resulting in nearly 3.2 million hospitalizations and 59,600 in-hospital deaths in children younger than 5 years. In infants younger than 6 months, RSV caused 1.4 million hospital admissions and 27,300 in-hospital deaths ^[3]. The estimated overall RSV mortality in 2015 was 118,200 deaths in infants younger than 5 years. Moreover, RSV is responsible for pulmonary morbidity and hospitalizations also in the elderly and high-risk adults ^[5], causing more than 17,000 deaths for underlying pneumonia and circulatory complications ^[6]. Risk factors for severe RSV infections in pediatric populations that may require hospitalization and Intensive Care Unit admission include prematurity, chronic lung disease of prematurity or bronchopulmonary dysplasia, hemodynamically significant congenital heart disease, congenital or acquired immunodeficiency, and severe neuromuscular disease.

2. Molecular Characteristics of Respiratory Syncytial Virus

RSV is an enveloped, non-segmented, negative-sense, single-stranded RNA virus of the Orthopneumovirus genus and Pneumoviridae family. The envelope of RSV includes four proteins associated with the lipid double layer: the matrix (M) protein, the small hydrophobic (SH) protein, and the two glycosylated surface proteins: F (Fusion) and G (attachment glycoprotein). The proteins, which are directly involved in infectivity and development of the respiratory disease, are F and G: the G protein determines the attachment of the virus to host epithelial cells, while the F protein is involved in the entry of the virus, through the fusion of viral and cellular membranes, as well as the subsequent insertion of the viral RNA into the host cell; the F protein is also responsible for fusion of infected cells with adjacent cells, resulting in the formation of the characteristic syncytia ^[7]. Moreover, both F and G proteins induce the neutralizing antibody immune response by the host ^[8]. Three types of epitopes have been identified in the G protein: (1) conserved epitopes, detectable in all viral strains; (2) group-specific epitopes, expressed only by the same antigenic group; and (3) strain-specific epitopes, which are present only in specific strains of the same antigenic group and expressed in the C-terminal hypervariable region of the G protein ectodomain ^[9]. The F glycoprotein is derived from an inactive precursor containing three hydrophobic peptides: (1) the N-terminal signal peptide, mediating translocation of the nascent polypeptide into the lumen of the endoplasmic reticulum; (2) the transmembrane region near the C-terminus, which links the F protein to the cell and viral membranes; and (3) the so-called fusion peptide, which inserts into the target cell membrane and determines the fusion process. The binding of the prefusion F protein to the cell surface is followed by its activation and structural changes, which determine the fusion of the membrane of the virus with the airway epithelial cells of the host and lead to the formation of syncytia. There are two major subgroups of RSV, A and B, usually both detectable during the same epidemic season, even if temporal and geographic clustering may occur ^[10]^[11]. RSV infections with Group A have a higher incidence and higher transmissibility than Group B ^[12]. The antigenic variability between the two groups is determined by differences in the G glycoprotein (35% homology between the G glycoprotein of strains A and B) ^[13]. For this reason, many antibodies targeting the G protein may be subtype-specific, while antibodies against the F protein have a neutralizing effect both against RSV A and B. Vaccine candidates against RSV use different antigenic targets ^[14]. Most vaccines in clinical trials use the F protein, because it is highly conserved and facilitates viral fusion with host cells. Current vaccine candidates use pre-F and post-F as vaccine antigens. Site zero (∅) of the pre-F protein has been recently discovered and is one of the major antigenic targets ^[15]. Other less frequent vaccine antigens, used alone or in combination with others, include the RSV envelope associated glycoprotein G and the SH protein, as well as the internal proteins: nucleocapsid (N), M and M2-1. Besides the F protein, the G protein is the only other target for neutralizing antibodies on the viral surface.

3. Prophylaxis measures

Prevention of RSV infection is based on primary and secondary prophylaxis. Preventive measures are critical because an etiologic treatment against RSV is not available. Primary prophylaxis is essentially based on hygienic measures aimed to prevent the diffusion of respiratory virus infections (handwashing, use of face masks in case of symptoms, disinfection of objects and surfaces) ^[16]. Secondary prophylaxis is based on the administration of monoclonal antibodies (mAbs) to high-risk patients during the epidemic season. The only commercially available mAb is palivizumab, while more recent ones are being studied in ongoing clinical trials ^[17]^[18]^[19]. No vaccine is currently available for active immunization against RSV, even if several are a matter of ongoing clinical trials ^[14]. One of the hardest challenges in the development of a safe and effective vaccine is enhanced respiratory disease (ERD), a side-effect that occurred in the 1960s subsequently to the administration of formalin-inactivated RSV vaccines ^[20]^[21]. Moreover, it is still a matter of concern if a vaccine determines absolute protection against RSV infections; encouraging data demonstrate that cell-mediated immunity, mucosal IgA, and serum neutralizing antibodies are inversely related to disease severity ^[14].

4. Target Populations

Considering the epidemiology of RSV, preventive measures are particularly useful for target populations. Currently, passive immunization with mAbs is reserved for high-risk infants ^[17], as detailed in national and international guidelines. Risk factors considered in the guidelines for prophylaxis include severe prematurity, congenital heart diseases, bronchopulmonary dysplasia, severe respiratory, and neuromuscular diseases. The clinical trials of vaccines against RSV are run on pediatric populations, old adults, or pregnant women with the aim to prevent RSV infections in high-risk populations (Table 1). RSV was also observed to affect long-term respiratory morbidity since young infants with RSV LRTI subsequently had an increased risk for asthma and recurrent wheezing ^[22]. For this reason, the development of a safe and effective vaccine may be useful to prevent the onset of respiratory morbidity if extended to cohorts of naive infants during the first months of life. Since severe RSV infections often involve newborns and very young infants, the strategy of vaccination during pregnancy may be useful to determine an effective immunity at early ages when active immunization is not feasible, as maternal antibodies are transferred efficiently through the placenta. Vaccines in clinical development are grouped into four categories: particle-based, vector-based, subunit, and live-attenuated or chimeric vaccines.

Table 1. Summary of the RSV vaccines in clinical development by the target population. Only the most advanced trial for a specific target group is reported. RSV: respiratory syncytial virus; NIAID: National Institute of Allergy and Infectious Diseases.

Target Population	Vaccine Name	Sponsor	Vaccine Type	Clinical Trial Phase
Pregnant women	ResVax	Novavax	Particle-based	III
	RSV F DS-Cav1 VRC-RSVRGP084-00-VP	NIAID	Subunit	I
	RSV vaccine	Pfizer	Subunit	II
	GSK3888550A	GlaxoSmithKline	Subunit	II
Children	RSV F nanoparticle	Novavax	Particle-based	I
	SynGEM	Mucosis	Particle-based	II
	Ad26.RSV.preF	Janssen	Vector-based	I/IIa
	ChAd155-RSV	GlaxoSmithKline	Vector-based	II
	MEDI-534	MedImmune (AstraZeneca)	Vector-based	I
	SeVRSV	NIAID	Vector-based	I
	RSV MEDI ΔM2-2	NIAID	Live-attenuated	I/II
	RSV LID ΔM2-2	NIAID	Live-attenuated	I
	RSV cps2	NIAID	Live-attenuated	I
	RSV LID cp ΔM2-2	NIAID	Live-attenuated	I
	RSV LID ΔM2-2 1030s	NIAID	Live-attenuated	I
	RSV D46/NS2/N/ΔM2-2-HindIII	NIAID	Live-attenuated	I
	RSV ΔNS2 Δ1313 I1314L	NIAID	Live-attenuated	I
	RSV 6120/ΔNS1; RSV 6120/F1/G2/ΔNS1	NIAID	Live-attenuated	I
	RSV ΔNS2/Δ1313/I1314L; RSV 6120/ΔNS2/1030s; RSV 276	NIAID	Live-attenuated	I/II
	RSV 6120/∆NS2/1030s	NIAID	Live-attenuated	I
	RSV ΔNS2/Δ1313/I1314L; RSV 276	NIAID	Live-attenuated	I
	RSV D46 cpΔM2-2	NIAID	Live-attenuated	I
	MEDI-559	MedImmune (AstraZeneca)	Live-attenuated	I/II
	MV-012-968	Meissa Vaccines	Live-attenuated	I
	rBCG-N-hRSV	Pontificia Universidad Catolica de Chile	Chimeric	I
Elderly	RSV F nanoparticle	Novavax	Particle-based	III
	SynGEM	Mucosis	Particle-based	II
	MVA-BN RSV	Bavarian Nordic	Vector-based	II
	VXA-RSVf oral	Vaxart	Vector-based	I
	Ad26.RSV.preF	Janssen	Vector-based	II
	PanAd3-RSV and MVA-RSV	ReiThera	Vector-based	I
	DPX-RSV	Dalhousie University	Subunit	I
	RSV vaccine	Pfizer	Subunit	II
	GSK3844766A	GlaxoSmithKline	Subunit	I

5. Particle-Based Vaccines

Particle-based vaccines are synthesized by self-assembling nanoscopic particles that expose multiple copies of a selected antigen on their surface and mimic the native virions: thanks to the high copy number of the selected antigen and the immune-boosting properties of the particle matrix, these vaccines elicit strong humoral and cellular immune responses ^[23]. Moreover, the lack of the viral genome required for replication makes them safe. To date, two nanoparticle-based RSV vaccines have been tested in clinical trials. The RSV F nanoparticle vaccine, developed by Novavax, is being evaluated in women of childbearing age, pre-school children (2–6 years old) and the elderly (≥ 60 years old). ^[24] In Phase I clinical trials, it has proven to be well-tolerated and highly immunogenic in all the target populations. ^[25]^[26]^[27]^[28] ResVax is a maternal RSV F nanoparticle vaccine with an aluminium phosphate adjuvant which is being developed to protect infants from RSV disease via maternal immunization. ResVax has been shown to be safe in a Phase II trial enrolling 50 healthy third-trimester pregnant women and to elicit RSV neutralizing antibodies and palivizumab-competing antibodies that are efficiently transferred to the infants. ^[29] This maternal vaccine has been the object a Phase III multi-country, randomized, placebo-controlled trial evaluating its efficacy against RSV-LRTI in infants born in the RSV season to 4363 women who received the vaccine or placebo between 28 and 36 weeks of pregnancy. ^[30] ResVax failed to meet the primary outcome of prevention of medically significant LRTI. However, it showed 44% efficacy in reducing RSV-LRTI hospitalization, 39.4% efficacy in reducing RSV-specific medically significant LRTI and 58.8% efficacy in reducing RSV-related severe hypoxemia in young infants (< 3 months of age). In addition, pneumonia was 49.4% less common in infants of the vaccinees than the placebo recipients. An additional Phase III clinical trial to confirm the efficacy of ResVax will thus be conducted by Novavax. ^[31] Regarding older adults, the non-adjuvanted RSV F nanoparticle vaccine failed to demonstrate efficacy in a 2015 Phase III clinical trial which enrolled 11,850 adults ≥60 years of age. ^[32] Novavax conducted a second Phase II clinical trial in the elderly to evaluate the safety and immunogenicity of single- or two-dose regimens of the RSV F vaccine with and without adjuvants (aluminium phosphate or Matrix-M1). The study showed that both adjuvants increased the magnitude, duration and quality of the immune response versus the non-adjuvanted RSV F vaccine. ^[33] These data support the inclusion of the RSV F vaccine adjuvant formulations in future elderly trials.

The other nanoparticle-based RSV vaccine that has been tested in clinical trials is SynGEM, developed by Mucosis. SynGEM is a mucosal vaccine containing the RSV F protein in the prefusion conformation bound to a bacterium-like particle (BLP) derived from Lactococcus lactis. BLP has the role to present the vaccine antigen in a more natural conformation and to boost the immune system of the virus. ^[34] The safety and tolerability of SynGEM have been evaluated in a Phase I trial and it was generally well-tolerated and induced persistent antibody responses in healthy adults. ^[35] However, no detectable RSV neutralizing antibodies were found, despite preclinical data that had shown protection. ^[36] Future studies are needed to optimize the immunogenicity of SynGEM.

Particle-based vaccines are promising both for young infants through the immunization of pregnant mothers and for the elderly. ResVax has already reached Phase III clinical trials for pregnant women, and hopefully new trials will soon allow its marketing approval. On the other hand, for elderly people, the use of RSV F vaccine adjuvant formulations in future trials may increase the magnitude, duration and quality of the induced immune response.

6. Vector-Based Vaccines

Vector-based vaccines use a carrier vector to deliver RSV antigens and induce an immune response against RSV components exploiting the adjuvant effect of the vector. Due to the chimeric nature of the vectors, there is no risk of reversion to wild-type RSV and of ERD. However, the presence of pre-existing anti-vector immunity or its potential development may challenge the clinical use of these vaccines. To date, eight RSV vector-based vaccines have been tested in clinical trials. The MVA-BN-RSV vaccine has been developed by Bavarian Nordic and it is based on a non-replicating modified vaccinia Ankara (MVA) virus; it displays the RSV surface proteins F and G (for both A and B subtypes) and two internal RSV proteins N and M2. It has passed phase I and II clinical trials, ^[37]^[38] and a phase III trial on elderly people is planned for 2021. ReiThera developed two novel, recombinant, viral-vectored vaccine candidates for RSV, PanAd3-RSV and MVA-RSV. Both vaccines use RSV F, N and M2 proteins as antigens, delivered, respectively, by a replication-defective simian Adenovirus (PanAd3) and MVA vector. PanAd3-RSV and MVA-RSV were well tolerated and immunogenic in healthy adults ^[39] and in the elderly ^[40], but their production has been halted since 2015. Three other virus-vectored vaccines use an Adenovirus vector to deliver RSV antigens. VXA-RSV-f, developed by Vaxart, is a molecularly adjuvanted Adenovirus serotype 5 based RSV vaccine encoding the F protein and is being developed for older adults, even if the results of an already concluded phase I trial have not been published yet. Janssen developed Ad26.RSV.Pre-F vaccine for the elderly and children, based on the human Adenovirus strain 26 vector expressing the F protein stabilized in the pre-fusion conformation. ^[41] A Phase II study evaluated the co-administration of a seasonal influenza vaccine with the Ad26.RSV.preF vaccine in 180 healthy elderly people, showing an acceptable safety profile and no evidence of interference in the immune response. ^[42] Results of two Phase I/IIa studies ^[43]^[44] evaluating the safety and tolerability of Ad26.RSV.preF in children should be published soon. Another Adenovirus-based vaccine, ChAd155-RSV, intended for children, is currently in clinical development. ^[45] Two vector based-vaccines use the parainfluenza virus (PIV) to display RSV antigens, with the aim to induce immunity against both viruses: MEDI-534 and the recombinant Sendai virus vectored RSV (SeVRSV). However, these vaccines are still under evaluation in Phase I trials. ^[46]^[47]

Vector-based vaccines are potentially good candidates for the pediatric population because there is no risk of reversion to wild-type RSV and of ERD. These vaccines are still in the initial stage concerning their evaluation. The eight vaccines that have been tested in clinical trials are based on MVA, Adenovirus, bovine PIV or Sendai Virus vectors. The MVA-BN-RSV vaccine is the only one that has passed Phase 2 clinical trial, and a Phase 3 trial in the elderly has been planned for initiation in 2021.

7. Subunit Vaccines

Subunit vaccines are created with RSV protein fragments. They are poorly immunogenic due to their non-replicating nature and their limited components; therefore, booster administration and adjuvants are often necessary to make them effective. ^[48] This type of vaccine primarily induces a CD4 T cell response, with a higher risk for vaccine-ERD in seronegative infants, ^[49]^[50] so subunit vaccines are under development only for pregnant women and older people that have already had a previous RSV infection and that are not a risk of developing ERD. ^[51] VRC-RSVRGP084-00-VP, a prefusion F-based RSV vaccine, has been tested in healthy adults with or without an aluminum adjuvant, with the aim of monitoring safety, tolerability, and immunogenicity. ^[52] Preliminary results that were published in 2019 are promising, ^[53] but the Phase I trial has recently been concluded (April 2020), and the results are expected to be published soon. Trials testing another subunit vaccine candidate (with and without adjuvant) on healthy adults of various age groups should be completed at the end of 2020 and in 2021. ^[54]^[55]^[56] Meanwhile, the Phase IIb trial, concluded in December 2019, recruited a group of healthy non-pregnant women (18–49 years old) to which this vaccine candidate was given together with diphtheria/tetanus/pertussis vaccine. ^[57] DepoVax (DPX)-RSV is a candidate based on the ectodomain of the SH protein, presented with a novel lipid-based formulation that ensures a prolonged exposure of the antigen; Phase I results are promising, ^[58] but Phase II has not yet started. BARS13 is a candidate based on the G glycoprotein: the Phase I study has involved healthy adult volunteers, but the results have not yet been published. ^[59] Two more candidates are under evaluation: GSK3888550A, with pregnant women as the target population, and GSK3844766A, designed for older adults. ^[60]

Subunit vaccines can be considered a safe choice: they do not contain live viruses that could return to a virulent state and they cannot induce an exceeding immune response. However, owing to concerns of ERD associated with protein-based vaccines, they are potentially good candidates only for pregnant women and the elderly. Observing the concluded trials and the studies in progress, induction of protective immunity, and obtaining F protein conformation stability remain the major unsolved problems for creating an effective subunit vaccine.

8. Live-attenuated and chimeric vaccines

Live-attenuated RSV vaccines (RSV-LAVs) are produced with versions of RSV that are able to replicate but have been modified to discourage severe disease. ERD has not been observed with RSV-LAVs or replicating vaccine vectors: for this reason, these candidates can be considered safe for naive-RSV infants. ^[49]^[61] RSV-LAVs have also other benefits: the ability to replicate in the respiratory tract despite the presence of maternal antibodies, the capacity to promote both a humoral and cellular immune response, and the possibility to be administered as nasal drops, which are less invasive and better tolerated in children. ^[62]^[63] Most vaccines are in Phase I and no candidates of this type have progressed beyond Phase II clinical trials. However, RSV-LAVs represent promising candidates worthy of further investigation.

The only chimeric vaccine candidate is rBCG-N-hRSV. ^[64] It consists of the bacillus Calmette-Guerin (BCG) vaccine expressing the nucleoprotein (N) of RSV. It is delivered via a BCG strain and induces a Th1 and a humoral response. It is the only LAV that combines protection against two respiratory pathogens, Mycobacterium tuberculosis and RSV. Furthermore, it could be safe for administration to newborn babies. A Phase I clinical trial on adults has been conducted, even if the results have not been reported yet. ^[65]

9. Conclusions

The development of an effective vaccine to protect high-risk groups from severe RSV infections is of critical importance but still challenging. Different antigens and vaccine formats should be considered for different target populations (children, the elderly, and pregnant women). To date, the formats that are being evaluated are particle-based vaccines, vector-based vaccines, subunit vaccines, and LAVs. Currently, the only vaccine that has reached Phase III clinical trials is a maternal RSV F nanoparticle vaccine, which showed efficacy in reducing hospitalization and RSV-LRTI in young infants, but did not meet the desired primary outcome, so future trials are needed to confirm its efficacy. The same vaccine with adjuvants was safe and immunogenic in the elderly, and future clinical trials will evaluate its efficacy. Only one vector-based vaccine has passed a Phase II clinical trial, and a Phase III trial in the elderly has been planned for initiation in 2021. Subunit vaccines are potentially good candidates for pregnant women and the elderly; induction of protective immunity and obtaining F protein conformation stability remain the major unsolved problems for creating an effective subunit vaccine. Most clinical trials for RSV-LAVs are only in Phase I, but these vaccines represent promising candidates worthy of further investigation as they are able to generate a robust immune response and, thanks to their safety and nature, can be administered also to infants. While waiting for commercially available safe and effective vaccines, immune prophylaxis in selected groups of high-risk populations is still mandatory. In young infants, combining the use of passive immunization via maternal vaccination or mAbs, followed by paediatric active immunization, may be effective to prevent severe RSV infection. Research on this topic is still of utmost importance.

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