Current status of developments in the field of respiratory syncytial virus vaccines

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Introduction

Among severe acute human respiratory diseases, respiratory syncytial virus (RSV) accounts for approximately 22% of cases. The number of deaths annually ranges from about 55,000 to 199,000, including 50,000–75,000 among children under 5 years of age [1, 2]. After RSV disease, no lasting immunity is formed, due to which the body is not resistant to subsequent infections [3, 4]. The reasons why this happens have not yet been established. In 2023, GlaxoSmithKline (UK) and Pfizer (USA) licensed subunit vaccines for the prevention of RSV infection in people over 60 years of age. Developer Moderna (USA) has submitted a messenger RNA (mRNA) vaccine for the prevention of RSV infection in the elderly. Many alternative vaccine candidates are in various stages of clinical trials.

The aim of the review is to summarize data on the development of RSV vaccines using different platforms and methodological approaches, the results of their preclinical studies in different animal models and clinical trials in different age groups.

General characterization of respiratory syncytial virus

RSV belongs to the order Mononegavirales, family Pneumoviridae (pneumoviruses), genus Orthopneumovirus. Until 2016, the virus was referred to the family Paramyxoviridae [5]. Another representative of the pneumovirus family is human metapneumovirus. Both pneumoviruses occupy a leading position in the structure of morbidity in children from birth to one year of age, the elderly and immunocompromised persons [6]. RSV infection is accompanied by severe pneumonias and bronchiolitis. According to expert estimates, in 2019, there were about 3.6 million human hospitalizations due to RSV infection and 101,400 related deaths among children aged 0–60 months worldwide [7].

RSV structure.
The RSV genome is unsegmented with a length of 15.2 bp, has a negative polarity, and encodes 11 viral proteins. The RSV viral envelope contains 3 transmembrane glycoproteins: attachment protein G, fusion protein F, and small hydrophobic protein SH. On the inner side of the viral envelope is the matrix protein M. The viral RNA is encapsulated by a nucleoprotein (N) and a large protein (L). Phosphoproteins P and M2-1 mediate transcription of viral RNA. M2-2 regulates viral RNA synthesis. The figure was adapted from [16].

RSV virions are pleomorphic: spherical forms with a diameter of 100–350 nm and filamentous forms with a length of up to 10 μm and a diameter of 60–200 nm are distinguished [8, 9]. The genetic material of RSV is represented by single-stranded RNA with negative polarity with a size of 15.2 kb. The RSV genome is unsegmented and contains 10 open reading frames encoding 9 structural and 2 non-structural proteins. The M2 gene contains 2 open reading frames and encodes 2 proteins: M2-1 and M2-2. The viral RNA is packaged inside a nucleocapsid of helical symmetry type, which is a ribonucleoprotein complex (RNP) (Figure). Replication occurs with the participation of an RNA-dependent RNA polymerase consisting of a large L protein and phosphoprotein P (cofactor L). P-, L- and M2-1-proteins participate in the transcription process [10, 11]. RSV refers to enveloped viruses whose genetic material is surrounded by a protein envelope and a lipid bilayer acquired from the host cell during virus assembly and budding. Matrix protein M is located between the capsid and the outer lipid bilayer. The integral membrane fusion protein F, attachment protein G, and small hydrophobic SH protein are embedded in the outer lipid bilayer. The F protein belongs to class I glycoproteins. Its main function is to allow virus entry into the target cell. Prior to interaction with the target cell, protein F is located on the surface of RSV in the “pre-F” conformation and acquires the “post-F” conformation due to the fusion of the viral and cell membrane [12].

The M2-2 protein is involved in replication and transcription [13]. NS1 and NS2 proteins are not part of the virion; their main role is to act as antagonists of α-/β-interferons, which are produced by the human body in response to viral infection [14, 15].

Prototypes of RSV vaccines

RSV was first discovered in 1956 [17], and for more than 60 years, work has been underway to develop a vaccine against RSV. The successful experience with formalin-inactivated vaccines against poliomyelitis, measles and parainfluenza was also applied to the first RSV vaccines, but the attempts were unsuccessful and new approaches to this problem were required.

Most RSV vaccines are developed on the basis of one of the most conserved RSV proteins, F, because this surface protein is the antigenic target for virus-neutralizing antibodies [18]. Approaches in which F-protein is stabilized in pre-F or post-F form have been developed [19, 20]. However, more often developers choose pre-F because virus-neutralizing antibodies are induced in greater amounts to this form of F-protein under conditions of natural infection or immunization [21].

History of RSV vaccines

In the 1950s, formalin inactivation of the virus was recognized as a successful technique [22]. In the United States in the 1960s, pilot trials of formalin-inactivated RSV vaccine (FI-RSV) were first conducted in infants and then large-scale clinical trials of the vaccine in children of different ages. The youngest cohort included children aged 2–7 months. Children in the experimental group (aged 4 months to 10 years) received 2 doses of FI-RSV intramuscularly, while those in the control groups received trivalent parainfluenza vaccine [23]. A 4-fold increase in RSV antibody levels was observed in 68% of those vaccinated with FI-RSV compared with control groups [23]. During the RSV circulation season, children receiving FI-RSV were more severely ill (7.9%) than controls (4.7%) [23]. An increased course of the disease was observed in children younger than 2 years of age [23]. Another study involved children aged 2–7 months; after FI-RSV vaccination, a 6-fold increase in neutralizing antibodies was observed compared with the control group [24]. In the winter period following the vaccination (1966/1967), 21 out of 30 children in the group of FI-RSV-vaccinated children became ill from natural exposure to RSV, whereas in the control group, it only happened in 5% of cases. Sixteen children in the FI-RSV group required hospitalization, while 2 infants died [24]. When comparing the results of trials among different age groups, it was found that children in the youngest group were at the most risk of severe disease progression when immunized with FI-RSV in the case of natural RSV infection. The development of vaccine-induced disease progression was found to be due to the fact that children were initially immunized with FI-RSV. One argument was that children who had previously been ill with RSV did not develop a state of immunopathology following immunization with FI-RSV after RSV infection. According to another argument, intramuscular injection of live RSV to RSV-naïve children did not show a protective effect of vaccination, but also did not develop a state of immunopathology. Thus, when developing RSV vaccine candidates, it is necessary to characterize in detail the phenotype of emerging memory T cells, as well as memory B cells with certain antigenic specificity.

After the unsuccessful FI-RSV clinical trials, attempts to develop a live attenuated vaccine began. The logic of this strategy is that during immunization, RSV will replicate exclusively in the upper respiratory tract, as a result of which the synthesized viral antigen will undergo intracellular processing and presentation on the surface of antigen-presenting cells, which will contribute to the formation of a balanced T- and B-cell immune response. When infants are vaccinated, the immune response will be formed locally in the respiratory mucosa where low levels of maternal IgG antibodies are observed [25]. The main advantage of using such technology is the method of administration by nasal spraying, which is recommended for use in pediatrics.

At the initial stages, certain difficulties were encountered in the creation of live attenuated vaccines due to the peculiarities of RSV cultivation, thermolability and its low viability. Live attenuated RSV can be obtained in several ways: by repeated passaging of the virus at reduced temperature, or by mutagenesis, which involves treatment of viruses with special mutagens, or by introducing mutations into the wild-type virus. To attenuate RSV, manipulations in SH or G proteins are commonly performed [26]. However, clinical trials of vaccine candidates obtained by mutagenesis have shown that a balance between sufficient viability of the vaccine strain and its immunogenicity cannot be achieved. In the 1980s, under the leadership of N.P. Leshchinskaya, a low-temperature strain obtained from Prof. P.M. Chanok (USA) was modified by conducting an additional 16 consecutive passages at a reduced temperature. During intranasal immunization with this vaccine candidate in children aged 1–2 years, clinical reactions of moderate severity were observed, which correlated with a 4-fold increase in specific anti-RSV antibodies. High antibody titers persisted only for 6-8 weeks after vaccination and then decreased to baseline levels [27]. Thus, due to attenuation mechanisms, it was not possible to obtain a ready-made vaccine preparation providing maintenance of long-term protective immunity. At the same time, the development of vaccine-induced pathology has not been shown with the use of live attenuated vaccines. Due to the failure of classical methods, alternative methods of producing RSV vaccines began to be developed.

Current approaches to the development of RSV vaccines

After the unsuccessful FI-RSV clinical trial, vaccine development in this area slowed down as new candidates underwent rigorous safety testing. On the other hand, the involvement of new approaches and technologies to combat RSV has led to notable advances in vaccine prophylaxis.

Vaccine candidates against RSV that have undergone clinical trials have been presented in detail in many reviews [28–31]. Note that such reviews should be updated every year due to the relevance and importance of the issue of vaccination coverage in populations that require RSV vaccine. It is important to select relevant animal species for preclinical trials to test the efficacy and safety of vaccines. In the case of RSV vaccines, a model of vaccine-induced enhancement of disease progression needs to be specifically studied. This problem is discussed in detail in the review by G. Zhang et al. [32]. The totality of a number of indicators characterizing innate and acquired immunity, which are associated with the severity of RSV infection in different animals, is presented in the review by S.B. Drysdale et al. [33]. This review collected data on trials of RSV vaccine candidates in laboratory animals, which were subsequently tested in humans.

mRNA vaccines

Nucleic acid-based vaccines, particularly mRNA vaccines, are an alternative to traditional vaccines. They consist of synthetic mRNA molecules with a structure that allows synthesizing the target protein of the antigen when it enters the target cell. When developing mRNA vaccines, special importance is given to mRNA delivery systems, since mRNA molecules are unstable and are subject to degradation by extracellular ribonucleases. Lipid nanoparticles are more commonly used, but other delivery strategies are being developed. For example, cell-penetrating peptide technology that allows mRNA to be delivered targeted to antigen-presenting cells for induction of an effective immune response [34].

The vaccine candidate mRNA-1345 (Moderna Inc., USA) encodes surface antigen F in a pre-F conformation, which is delivered using lipid nanoparticles (LNPs) [35]. The Spikevax vaccine (Moderna Inc.), used to immunize patients 12 years of age and older against COVID-19, was developed based on the results obtained from mRNA-1345 studies [36]. In 2024, a mRNA-1345 vaccine candidate called mResvia was approved by the U.S. Food and Drug Administration (FDA) for immunization of patients over 60 years of age. The developer initially created several vaccine candidates containing the mRNAs required to elicit expression of protein F in the pre-F conformation (mRNA-1777 and mRNA-1172) [37, 38]. The vaccine candidate mRNA-1345 was derived from genetic modification of the mRNA within mRNA-1172 performed to increase F protein expression and alter its distribution in infected cells [39, 40]. In 2023, the results of a phase III clinical trial (ConquerRSV, NCT05127434) of mRNA-1345 (subsequently mResvia) were announced, according to which the efficacy of this vaccine was 83.7%. The study evaluated the clinical effect of immunization against two symptoms associated with lower respiratory tract disease in humans caused by RSV [41]. Clinical trials of the vaccine candidate mRNA-1345 in children aged 5 months to 2 years are currently underway (NCT05743881). Clinical trials are underway for the safety and efficacy of mRNA-1345 in immunized pregnant and postpartum infants (NCT06143046).

In 2024, phase I clinical trial studies of the world’s first bivalent mRNA vaccine IN006 (InnoRNA, China), approved not only by China’s National Drug Administration but also by the FDA, began. This mRNA vaccine targets the expression of F-protein in the pre-F conformation of both RSV serotypes, A and B. Lipid nanoparticles are used as delivery system¹.

Phase I and II clinical trial studies of mRNA vaccine candidates LNP CL-0059 and LNP CL-0137 mRNA vaccines against RSV (Sanofi, France) are currently underway. The study description reports that two different lipid nanoparticles are being tested for mRNA delivery (NCT05639894).

Vector vaccines

Vector vaccines are based on carrier vectors for delivery of RSV antigens to target cells and induction of an immune response against the virus antigens in the insert. RSV vaccines using modified Ankara smallpox vaccine viruses (MVA), adenoviruses, bovine parainfluenza viruses, Sendai virus and influenza viruses as vectors are currently undergoing clinical trials.

In studies at the Institute of Experimental Medicine (Russia), live influenza vaccine (LIV) serves as the vector. Three polyepitope cassettes of RSV were selected for integration into the genome of attenuated influenza virus [42]. The first cassette contains the fragment F243-294, with the antigenic site II of the RSV F-protein to which the monoclonal antibody Palivizumab binds. The other two cassettes are targeted primarily at the activation of cytotoxic T lymphocytes during vaccination and are represented by epitopes within the M2-1 protein of RSV.

Experiments on laboratory mice revealed that recombinant vaccine strains of RSV encoding a polyepitope T-cell cassette induce the development of a stable, fully functional RSV-specific systemic and local CD8⁺ T-cell immune response that protects immunized animals from RSV reproduction in the lungs. Immunization with a T-cell vector vaccine has been shown to induce the formation of tissue-resident memory T cells to the built-in immunodominant CD8⁺ T-cell epitope [43]. At the same time, the incorporation of the RSV F243-294 fragment into the HA molecule of influenza virus was found to be insufficient for induction of protective levels of RSV-specific antibodies in mice. However, immunization with such a chimeric virus prevents the development of RS-induced pulmonary pathology [44].

At the Smorodintsev Research Institute of Influenza (Russia), the developers use a modified influenza virus A/PR/8/34, weakened by shortening the NS1 protein to 124 amino acid residues, as a vector for delivery of the RSV F-protein transgene containing antigenic sites II and IV [45]. The resulting vaccine candidate RSV/Flu-01E has undergone phase I clinical trials (NCT05970744) in volunteers of two age groups — 18–59 years of age and elderly over 60 years of age and phase II clinical trials in volunteers over 60 years of age.

The vaccine candidate MVA-BN-RSV (Bavarian Nordic A/S, Denmark) is engineered based on modified Ankara vaccinia virus (MVA). The recombinant vaccinia strain MVA expresses F- and G-proteins of both subtypes (A and B) of RSV, as well as N- and M2-proteins of RSV. The results of phase I clinical trials showed that immunization with MVA-BN-RSV induced the production of humoral and cellular immune response against RSV in elderly (50–65 years old) and in adults (18–49 years old) [46]. In a phase II clinical trial (NCT02873286), MVA-BN-RSV was found to be well tolerated by immunized individuals over 55 years of age and resulted in a durable immune response that persisted for at least 6 months after a single vaccine administration. The results of a second immunization one year after the first immunization showed that the level of T-cell immune response was higher or similar to that observed after the first immunization [47]. However, in a phase III clinical efficacy trial in individuals over 60 years of age, it was recognized that MVA-BN-RSV immunization did not meet the study endpoint and was ineffective².

In the RSV001 study (NCT01805921), two recombinant vaccines were researched: PanAd3-RSV and MVA-RSV (ReiThera, Italy). PanAd3-RSV was developed based on monkey adenovirus, while MVA-RSV was based on modified Ankara vaccinia virus [48, 49]. The following proteins were used as RSV antigens: F (F₀ ΔTM — full-length, F — without transmembrane domain), N and M2-1, which are delivered to the target cell by replication-defective monkey adenovirus vector (PanAd3) or MVA vector [50]. The vaccine candidates PanAd3-RSV and MVA-RSV administered in different combinations by different routes (intramuscular and intranasal administration of PanAd3, intramuscular administration of MVA) were well tolerated and immunogenic in adult humans (18–50 years of age) [51]. In the RSV001 study (NCT01805921), induction of humoral and cellular immune response after immunization was recorded in elderly individuals (60–75 years) [52].

The vaccine candidate VXA-RSV-f (Vaxart, USA) was developed based on adenovirus subtype 5 expressing RSV F-protein and a molecular adjuvant in the form of double-stranded RNA [53]. A phase I clinical trial (NCT02830932) was conducted in humans aged 18–49 years and ended in 2018. Results to date have not been published³.

The vaccine candidate Ad26.RSV.Pre-F (Janssen, Belgium) was designed on the basis of adenovirus type 26 expressing F-protein in the pre-F conformation [54]. In phase I and II clinical trials (NCT03502707), different vaccine administration regimens, including combination with recombinant F-protein, were tested on the elderly (over 60 years of age). Those immunized with the combined regimen showed a more intense production of humoral and cellular immune response compared to the group injected with Ad26.RSV.preF alone [55]. A phase II (NCT03339713) clinical trial evaluated the combined administration of Ad26.RSV.preF and seasonal influenza vaccine (Fluarix, GSK). The vaccine was shown to demonstrate an acceptable safety profile and no evidence of immune interference in the elderly (over 60 years of age) [56]. A phase I/a (NCT03303625) clinical trial (NCT03303625) of Ad26.RSV.Pre-F showed that immunization in RSV-seropositive children aged 12–24 months and adults (18–50 years) produced RSV-specific neutralizing antibodies that persisted for 7 months. In addition, those immunized with Ad26.RSV.Pre-F were less susceptible to RSV infection in vivo [57].

ChAd155-RSV (GlaxoSmithKline, UK) is based on chimpanzee adenovirus-155 and encodes RSV proteins F, N and M2-1 [58]. The vaccine candidate was pre-tested on calves, in which the mechanisms of immune response to RSV are closest to children. After calf vaccination, neutralizing antibodies to RSV were induced, there was no evidence of vaccine-mediated disease enhancement, and protection against bovine RSV was demonstrated [59]. In a phase I/II clinical trial (NCT02927873), RSV-seropositive children aged 12–23 months were immunized with ChAd155-RSV and followed for 2 years after vaccination. As a result, a dose-dependent increase in RSV neutralizing antibody titers was observed [60].

The published results of phase I/II clinical trials (NCT03636906) of ChAd155-RSV in children aged 6–7 months showed that immunization caused induction of the humoral immune response in immunized individuals, and no signs of vaccine-mediated disease enhancement developed [61].

The vaccine candidate MEDI-534 (MedImmune, currently AstraZeneca, USA) is based on a chimeric bovine and human parainfluenza virus type 3 (PIV3) expressing the RSV F-protein [62]. In a phase I clinical trial (NCT00345670) involving children with previous RSV, this live attenuated intranasal vaccine was safe but immunogenicity was very low [63]. However, when tested in RSV seronegative infants, the target population for this vaccine, MEDI-534 was well tolerated by the immunized and induced an immune response against RSV in approximately 50% of cases and against the PIV3 vector in all cases [64].

The vaccine candidate SeVRSV (NIAID, USA) is a replication-capable Sendai virus, a strain of murine parainfluenza virus type 1 (PIV-1) that expresses the F-protein of RSV. Based on a phase I clinical trial (NCT03473002), it was found that immunization with SeVRSV in humans aged 18–45 years results in a low level of immune response to RSV. This fact is explained by the presence of pre-existing immunity to the vector in this age group [65].

Live attenuated vaccine

There are several approaches to the development of live attenuated RSV vaccines. The traditional approach is based on the sensitivity of the virus to certain reproductive temperatures or chemical agents. An alternative approach is based on the use of reverse genetics techniques to produce attenuated replication-competent virus. Vaccines developed using reverse genetics techniques have been tested on infants as young as 4 weeks of age [66, 67]. Live attenuated vaccines are considered safe for children who have not previously had RSV, as their use does not cause a vaccine-induced enhancement of the disease course after RSV infection [24, 68]. Furthermore, live attenuated vaccines are usually available as nasal drops. Once in the respiratory tract, they replicate there, regardless of the presence of maternal antibodies, ensuring the formation of both humoral and cellular immune response [69, 70].

One way to obtain an attenuated strain of RSV is deletion of the SH gene. Several vaccine variants have been developed in this way.

The vaccine candidate rA2cp248/404/1030∆SH was designed with several temperature-sensitive mutations, with mutations obtained by passaging the virus at low temperature, and with a deletion of the SH gene. In an immunogenicity study of rA2cp248/404/1030∆SH on RSV-seronegative children 1–2 months of age, high immunogenicity of the vaccine was observed. The vaccine candidate was weakly immunogenic in RSV-seropositive children and adults [67].

The vaccine candidate MEDI-559 (MedImmune, currently AstraZeneca, USA) differs from the previous candidate by the presence of 39 synonymous nucleotide substitutions [71]. Both vaccine candidates, rA2cp248/404/1030∆SH and MEDI-559, were tested on healthy children aged 5–24 months who had no previous history of RSV. However, the results of the studies revealed insufficient genetic stability of both candidates, a tendency to reversion of individual point mutations leading to decreased temperature sensitivity, which was observed in more than one third of the vaccine virus isolates [71, 72].

Vaccine candidate RSVcps2 (NIAID, NIH/Wyeth, USA) is a stabilized version of the MEDI-559 vaccine. According to the results of phase I clinical trials (NCT01852266 and NCT01968083) in children aged 6–24 months, RSVcps2 was well tolerated and had moderate immunogenicity [73].

An attenuated live vaccine phenotype can be achieved by deletion of the M2-2 RSV gene. Deletion of M2-2 results in a shift in the viral RNA synthesis program, which increases the level of viral RNA transcription and viral antigen expression, but decreases viral genome replication [74].

Two vaccine candidates MEDI/ΔM2-2 (NIAID, USA) and LID/ΔM2-2 (NIAID, USA) were evaluated [75, 76]. Both variants contain the M2-2 deletion and both are derived from different RSV cDNA derivatives of the same A2 subtype, differing by 21 nucleotide sequences located at different sites in the genome. In the vaccine candidate LID/ΔM2-2, non-translated regions of the SH gene were deleted and synonymous substitutions (silent mutations) were added to the SH protein of RSV. The inserted mutations do not affect the phenotype of the assembled virus, as confirmed by experiments in mice [77]. Vaccination with both candidates stimulated the production of RSV-neutralizing antibodies, with LID/ΔM2-2 considered more effective because it provided a slight increase in replication. On average, the peak titer of virus secreted by vaccinated individuals was 100-fold higher in those who received LID/ΔM2-2 [75, 76]. Therefore, it was proposed to modify the vaccine candidate LID/ΔM2-2 by introducing either an additional mutation in the L protein causing temperature sensitivity or 5 point mutations in the N, F, and L proteins, which were previously found in the attenuated RSV strain and associated with adaptation to reduced temperature. Because of active replication, the LID/ΔM2-2 candidate was modified. However, the vaccine candidate LID/cp/ΔM2-2 was subsequently found to be hyperattenuated, had a low infectious titer, and stimulated antibody production in only a fraction of clinical trial participants [76].

The vaccine candidate LID/ΔM2-2/1030s was created by adding the genetically stabilized mutation 1030s. The results of phase I clinical trials (NCT02237209, NCT02040831) on children aged 6–24 months established a high titer of neutralizing antibodies in immunized individuals, which was clinically equivalent to the antibody titer produced by natural RSV infection, according to expert estimates [78].

A modified LID-based vaccine candidate, D46/NS2/N/ΔM2-2-HindIII, was engineered to achieve a similar phenotype to the MEDI/ΔM2-2 candidate. Overall, it was more attenuated than LID/ΔM2-2 but exhibited high viral titers [76].

In a study by S.S. Stobart et al., a recombinant strain of RSV OE4 (RSV-A2-dNS1-dNS2-ΔSH-d_Gm-G_snull-line19F) with increased levels of antigen F in the pre-F conformation was shown to exhibit thermostability and immunogenicity despite strong attenuation in the airways of cotton rats [79].

Another promising strategy involves NS1 and NS2 deletions that disrupt the host cell TGFβ signaling pathway, transforming the immune response to enhance viral replication [80, 81].

Phase I phase I clinical phase trials (NCT03227029 and NCT03422237) of the RSV/ΔNS2/Δ1313/I1314L vaccine candidate (Sanofi, France) have established the immunogenicity and protective efficacy of the vaccine in RSV-seronegative children aged 6-24 months [82]. A phase III clinical trial (NCT06252285) of the RSV/ΔNS2/Δ1313/I1314L vaccine candidate is currently underway with 6300 children aged 6–22 months.

Subunit vaccines

Most subunit RSV vaccines under development contain a surface F-protein in the pre-F conformation [83]. The immunogenicity of such vaccines is enhanced by the use of adjuvants or multiple immunizations [84]. Given the composition of subunit vaccines and the failure of FI-RSV clinical trials, special attention is paid to safety. Immunization with FI-RSV has been found to result in insufficient production of antibodies with neutralizing activity. Subsequent signs of vaccine-mediated disease enhancement are attributed, among other things, to poor stimulation of Toll-like receptors in B-cells, which entails a lack of affinity maturation of antibodies [85]. Thus, affinity maturation due to Toll-like receptor stimulation is a key factor in helping to prevent a vaccine-induced disease amplification state. Subunit vaccines are currently being developed for pregnant women, the elderly, and adolescents who have previously had RSV to reduce the risk of vaccine-mediated disease enhancement [30, 86].

The vaccine candidate DS-Cav1 (NIAID, USA) is based on the F-protein in the pre-F conformation [87]. In a phase I clinical trial of DS-Cav1 in adults aged 18-50 years (NCT03049488), it was found that immunized individuals showed an increase in RSV-F-specific antibodies with neutralizing activity. Moreover, the level of neutralizing antibodies was above the baseline level for 10 months after immunization [88]. In this study, aluminum hydroxide was used as an adjuvant.

The vaccine candidate DepoVax-RSV or DPX-RSV (ImmunoVaccine Technologies Inc., Canada) was developed based on the ectodomain of the SH (SHe) protein of RSV. This peptide is administered with DepoVax adjuvant, which ensures prolonged exposure of the antigen to the immune system. According to the results of Phase I clinical trials (NCT02472548), an increase in anti-SHe-specific antibodies was recorded after DPX-RSV administration in immunized people aged 50–64 years old [89].

In May 2023, the FDA approved the first Arexvy vaccine (GlaxoSmithKline, UK) for people over 60 years of age. This vaccine contains RSV F-protein in a pre-F conformation and is administered together with adjuvant AS01E to provide a protective effect against RSV subtypes A and B. According to the results of phase I clinical trials (NCT03814590 and NCT04090658) of Arexvy on the elderly aged 60–80 years, it was found that immunization promoted the formation of RSV-specific IgG antibodies, neutralizing antibodies, and CD4⁺ T cells which were detectable in the immunized after one year [90, 91]. The results of a phase II clinical trial (NCT04657198) documented an increase in immunization efficacy after revaccination of study participants 1.5 years after the first immunization [92]. A 2b randomized open-label efficacy and safety study of Arexvy was announced between 2023 and June 2025. Participants in the study included people aged 18 years and older who had undergone lung or kidney transplantation and were at increased risk of lower respiratory tract disease compared to healthy people aged 50 years and older (NCT05921903). One study in a phase III clinical trial (NCT04732871) reported an increase in neutralizing antibody titers to RSV and cases of immunization-induced adverse events [93]. The most recently published data from a phase III clinical trial (NCT04886596) evaluated the efficacy of Arexvy immunization in 24,967 participants during 2 epidemiologic seasons of RSV circulation. The efficacy of Arexvy immunization was about 67.2% for lower respiratory tract disease and about 78.8% for severe lower respiratory tract disease caused by RSV [94].

Based on the interim results of a phase III clinical trial (NCT05035212), another subunit vaccine for the prevention of RSV infection in the elderly, Abyrsvo (Pfizer, USA), which contains RSV F-protein in the pre-F conformation, was approved. According to the results of phase I clinical trials of Abyrsvo, immunized people produced RSV-specific IgG antibodies to A- and B- strains of RSV [95]. In phase II clinical trials Abyrsvo was tested in non-pregnant and pregnant women (NCT04071158 and NCT04032093). A phase III clinical trial (NCT04424316) in pregnant women has recently been completed. Infants born to mothers immunized during pregnancy were found to have a lower incidence of RSV-associated diseases than those born to unimmunized mothers [96]. The phase III clinical trial RENOIR (NCT05035212) determined that the efficacy of prevention of RSV-induced lower respiratory tract disease was about 66.7% [97]. The MONET (NCT05842967) phase III clinical trial immunized people aged 18-59 years with chronic diseases at risk for severe RSV. The vaccine was well tolerated, safe and immunogenic [101]. Overall, the rates of RSV-specific neutralizing antibodies in immunized individuals from the MONET study were not lower than those in immunized older adults over 60 years of age from the RENOIR study (NCT05035212).

Vaccines based on virus-like particles

Vaccines based on virus-like particles are considered to be a subclass of subunit vaccines. These vaccines are synthesized by self-assembly of nanoparticles that exhibit multiple copies of a selected viral antigen on their surface. A high level of humoral and cellular immune response is achieved not only due to the multiple repetition of antigen sites, but also due to the immunostimulatory properties of the matrix for immobilization of nanoparticles [99]. The absence of viral genome in the composition of these vaccine candidates makes them safe due to their inability to reproduce viable virions.

The vaccine candidate ResVax (Novavax, USA) is based on the F-protein of RSV and is a vaccine based on virus-like particles. The vaccine is being developed to protect infants by vaccinating expectant mothers, children aged 6 months to 5 years and elderly individuals over 60 years of age. A phase II clinical trial (NCT02247726) found that immunization of healthy pregnant women induced the production of neutralizing antibodies to RSV that were effectively transmitted to the newborn [100]. The success of this phase of research led to the inclusion of the vaccine candidate ResVax in the PREPARE study program (a multicenter, randomized, placebo-controlled phase III study, NCT02624947). The clinical trial involved follow-up of infants born at the very beginning of the epidemic season of RSV circulation from mothers immunized with ResVax in the third trimester [101]. It turned out that ResVax immunization was not effective. Despite this, it was stated that ResVax reduced hospitalizations in children associated with RSV-related lower respiratory tract infections by 44%. Furthermore, a 39.4% reduction in RSV-specific lower respiratory tract infections and a 58.8% reduction in RSV-associated hypoxemic respiratory failure in infants younger than 3 months of age have been reported [101].

The vaccine candidate SynGEM (Virtuvax, The Netherlands) is a mucosal vaccine containing an F-protein in a pre-F conformation bound to bacteria-like particles derived from Lactococcus lactis. Due to the bacteria-like particles, the RSV vaccine antigen appears in a more natural conformation and an enhanced immune response against RSV is observed [102]. Clinical trials of the vaccine without adjuvant were ineffective in the elderly group. Vaccination contributed to a 61% reduction in hospitalizations in the elderly with chronic obstructive pulmonary disease. According to the results of phase I clinical trials, no increase in neutralizing antibodies in sera, which recognize epitopes within the unique Ø site of the F-protein, was observed in immunized individuals [103, 104]. Nevertheless, the vaccine induced the production of palivizumab-like antibodies. Currently, clinical trials of this vaccine have been suspended.

Vaccine candidate V-306 (Virometrix, Switzerland) contains a peptide consisting of mimetics of the F-protein RSV mimicking antigenic site II. The peptide is conjugated to synthetic nanoparticles made of self-organizing lipopeptides. In a Phase I clinical trial (NCT04519073), the V-306 vaccine was found to be safe and immunogenic in healthy women aged 18–45 years old [105].

Conclusion

RSV is the cause of severe respiratory diseases in children of the 1st year of life, immunocompromised people and the elderly [106, 107]. The clinical presentation of RSV varies from mild upper and lower respiratory tract infections to pneumonias and bronchiolitis in children.

To date, the FDA has approved the use of 3 vaccines for the prevention of RSV infection in humans. The bivalent subunit vaccine Abrysvo (Pfizer, USA) is approved for use in pregnant women and the elderly. Arexvy subunit vaccine (GlaxoSmithKline, UK) and mRESVIA mRNA vaccine (Moderna, USA) are approved for use in elderly people over 60 years of age.

The development and efficacy studies of RSV vaccines for children, who represent the main target group, are ongoing. In this case, the main problems include the need to vaccinate infants at an early stage (2-4 months), the revealed effect of enhancing the course of the disease associated with the introduction of FI-RSV with alum adjuvant, and difficulties in achieving the required indicators of prophylactic efficacy. For a long time, the only specific treatment for RSV infection was the monoclonal antibody drug Palivizumab, usually prescribed to people at high risk of severe forms of the disease. In this case, a significant factor is the high cost of treatment with this drug, which makes it unaffordable in countries with the highest incidence of RSV infection [108].

In 2022–2023, the monoclonal antibody drug Nirsevimab (AstraZeneca, UK; Sanofi, France) was approved and recommended for children in cases of severe RSV infection and its complications [109].

Vaccines are currently being developed for women of reproductive age and pregnant women to protect a cohort of naïve infants, as well as to protect the elderly and children. Vaccines based on virus-like particles, vector, subunit and live attenuated vaccines are in various phases of clinical trials.

Up-to-date information on vaccine candidates in preclinical studies is presented in Table 1. Information on candidates studied in different phases of clinical trials is summarized in Table 2.

Table 1. Results of preclinical trials of RSV vaccine candidates

Note. i.n. — intranasally; i.t. — intratracheally; i.m. — intramuscularly; s.c. — subcutaneously; or. — orally; i.p. — intraperitoneally; scar. — scarification

Table 2. Overview of vaccines in various stages of clinical trials

Note. C. — Children; E. — Elderly (lower threshold 50, 55 or 60 years); A. — Adults (from 18 years, upper threshold varies).

¹ Innorna Announces First Participant Dosed in Phase 1 Clinical Trial of Investigational Bivalent RSV mRNA Vaccine IN006; 2024. Available at: https://innorna.com/news/330.html

² Bavarian Nordic. Bavarian Nordic Provides Update on RSV Vaccine Program. URL: https://www.bavarian-nordic.com/investor/news/news.aspx?news=6808

³ ClinicalTrials.gov. Dose-Ranging Trial of Safety & Immunogenicity of an Oral Adenoviral-Vector Based RSV Vaccine (VXA-RSV-f). URL: https://clinicaltrials.gov/study/NCT02830932

About the authors

Tatiana S. Kotomina

Author for correspondence.
Email: kotomina@iemspb.ru
ORCID iD: 0000-0001-9999-089X

Cand. Sci. (Biol.), senior researcher, Laboratory of immunology and prevention of viral infections, Smorodintsev virology department

References

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1. JATS XML

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2. RSV structure. The RSV genome is unsegmented with a length of 15.2 bp, has a negative polarity, and encodes 11 viral proteins. The RSV viral envelope contains 3 transmembrane glycoproteins: attachment protein G, fusion protein F, and small hydrophobic protein SH. On the inner side of the viral envelope is the matrix protein M. The viral RNA is encapsulated by a nucleoprotein (N) and a large protein (L). Phosphoproteins P and M2-1 mediate transcription of viral RNA. M2-2 regulates viral RNA synthesis. The figure was adapted from [16].

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