Introduction

Respiratory syncytial virus (RSV), discovered in 1956, is a negative-sense single-stranded RNA virus belonging to the Pneumonaviridae family. RSV is highly contagious and represents a major burden of respiratory disease worldwide, causing severe and even fatal respiratory infections and bronchiolitis, especially in the elderly (≥ 65 years), young children (< 5 years), and those with underlying chronic diseases (e.g., pulmonary and circulatory diseases) [1]. In 2019, globally, there were 33 million events of RSV-associated acute lower respiratory tract infection (uncertainty range, 2.54 to 446 million) and 1.01 million total RSV-attributable deaths (84 500 to 125 200) in young children [2].

There has been a long road with multiple obstacles to develo** a safe and effective RSV vaccine. Earlier vaccines provided insufficient protection as they used the post-F conformation as the vaccine antigen. This is because multiple unique antigenic sites are exposed on the surface of the F protein before RSV fuses with the host cell membrane. Following fusion, the F protein adopts a very different confirmation in which several antigenic sites are no longer exposed [3]. Thus, the stabilization of the pre-F conformation has made it possible to develop effective subunit vaccines [4]. On May 3, 2023, the U.S. Food and Drug Administration (FDA) approved the world’s first RSV vaccine (developed by GSK) and on May 31, 2023, the Pfizer vaccine, both for adults older than 60 years of age. Both vaccines use a prefusion stable variant of the F protein. RSV prefusion F vaccine has become a hot spot in the research of vaccines against RSV. A large number of clinical studies have investigated its protective efficacy. However, to date, no systematic reviews have been performed on the efficacy, immunogenicity and safety of RSV prefusion F vaccine. In this review, we compared the protective efficacy, antibody titer levels, and adverse reaction profiles of different RSV prefusion F vaccines between immunized individuals and controls.

Methods

This systematic review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [5].

Search strategy

In September 2023, in accordance with the study protocol, we conducted searches across several databases, including Medline via PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov, to identify articles published up to September 8, 2023. The following MeSH (Medical Subject Heading) terms and search terms were used: (“Respiratory Syncytial Viruses or RSV”) AND (“vaccine or vaccination or efficacy or adverse event”).

Eligibility criteria

The inclusion criteria included: (1) individual study populations being at least twenty cases; (2) the use of prefusion F protein as an immunogen is explicitly stated; (3) clinical trials in human subjects have been published. No language restrictions were imposed on the publications. To enhance the validity of the data, we excluded non-peer-reviewed articles from preprint databases.

Study selection

In this review, we employed a two-stage approach for screening, initially assessing titles and abstracts followed by full-text articles. Two researchers independently reviewed each title, abstract, and full text, with any discrepancies resolved through consensus with a third researcher. The efficacy of the vaccines were assessed on three endpoints. First, the efficacy of the vaccine in preventing RSV-associated acute respiratory illness which was defined as the ability of the vaccine to prevent RT-PCR-confirmed RSV infection within seven days of acute respiratory illness symptom onset. Second, the efficacy of the vaccine in preventing medically attended RSV-associated lower respiratory tract illness which was defined as at least two symptoms or signs of acute respiratory infection lasting at least 24 h (cough, abnormal breathing, fever, lethargy, or any other respiratory symptom of concern). Third, the efficacy of the vaccine in preventing medically attended severe RSV-associated lower respiratory tract illness which was defined as tachypnea (respiratory rate ≥ 70 breaths per minute in infants younger than two months [60 days] of age or ≥ 60 breaths per minute in those between two months and 12 months of age); SpO2 < 93% while the infant was breathing ambient air; use of oxygen delivered through a high-flow nasal cannula or mechanical ventilation; admission to an intensive care unit for more than 4 h; and unresponsiveness or unconsciousness. The efficacy of the RSV vaccine was based on assessing its efficacy during the first RSV season (about 6 months) after vaccination. All the efficacy endpoints were considered if they occurred at least seven days after the full regimen of the vaccine.

Data extraction

Two researchers extracted data using a predefined extraction form. Subsequently, all key extracted data underwent review and quality checking by the same two researchers at the conclusion of the data extraction phase. Data on study characteristics encompassed information regarding the setting, primary and secondary outcomes, study design, sample size, and exclusion and inclusion criteria. Participant data included details such as sex, age, and relevant medical history, including disease and treatment history. Intervention-related data consisted of the vaccine type and brand, dosing schedule, the number of participants receiving each type and brand of vaccine, and the median or mean interval between doses. Data pertaining to immunogenicity results included details such as the assay type, the specific antibody measured, T cell response, the method of measurement, intervals of sample collection, and the number of measurements conducted.

Risk of bias assessment

Two investigators independently evaluated the risk of bias in the included studies based on critical criteria, including random sequence generation, allocation concealment, blinding of participants, personnel, and outcomes, incomplete outcome data, selective outcome reporting, and other potential sources of bias, following the methods recommended by The Cochrane Collaboration. The risk of bias graph was generated using Revman 5.4 software. The following judgments were used: low risk, high risk, or unclear. Authors resolved disagreements by consensus and further article review if necessary.

Data analysis

We used RevMan 5.4 statistical software to pool dichotomous outcomes, with the risk ratio (RR) and its 95% confidence interval (CI) as the effect measures. RR < 1 implies a lower risk in the vaccinated group compared to the control group, and P < 0.05 indicates that this difference is statistically significant. The I2 statistic was used to estimate the level of heterogeneity, and significant heterogeneity was considered when the I2 value was > 50%. Vaccine efficacy was calculated using the fixed effects RR. This study applied the accepted statistical vaccine efficacy formula, (1 − RR) ×100, for calculating the pooled vaccine efficacy from the pooled RR. We conducted visual examinations of funnel plots and utilized Egger’s test to assess potential publication bias. Additionally, we employed the trim-and-fill analysis to evaluate the effect of publication bias on the pooled effect size estimates. Influence analysis, which constitutes a form of sensitivity analysis, was performed to identify the impact of individual studies on the combined estimates.

Results

Study selection and study characteristics

A total of 10,554 records were initially retrieved from the database. After screening titles and abstracts, we evaluated 298 full texts of potentially eligible reports; a total of 22 articles were included, involving 78,990 participants (Fig. 1) [6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27]. Of the 22 eligible studies, eight (36%) studies were analyzed to evaluate the efficacy of RSV prefusion F vaccines, 20 (91%) studies were analyzed to evaluate immunogenicity, and 22 (100%) studies were analyzed to evaluate safety (Table 1). The included studies reported data for four vaccine types: 15 (68%) for subunit vaccines, five (23%) for adenovirus vaccines, one (4%) for mixed adenovirus and subunit vaccines, and one (4%) for mRNA vaccines. The 22 included studies involved diverse populations, with 10 involving older adults over 60 years of age, 4 involving pregnant women, 3 involving non-pregnant women, and 7 involving healthy adults. The included studies involved more than 20 countries or regions, with 11 (50%) studies being multinational, six (27%) studies from Spain, followed by two (9%) studies from Australia, and one each from Japan, Canada, and the United Kingdom. 12 (55%) of the eligible studies were observer-blinded and 10 (45%) were double-blinded.

Fig. 1
figure 1

Flowchart of study selection

Full size image
Table 1 Characteristics of studies included in meta-analysis
Full size table

Risk of bias assessment of included studies

Twenty-two studies used Cochrane collaboration tools for independent risk of bias assessment, only two studies had high risk in blinding of outcome assessment, and most studies were low risk in all evaluated domains (Fig. 2). Overall, all of these included studies had a low risk of bias, with blinding and other biases in outcome assessment being the main risk factors.

Fig. 2
figure 2

Risk of bias graph: review authors’ judgements about each risk of bias item presented as percentages across all included studies

Full size image

Efficacy of RSV prefusion vaccine

Six (27%) studies were included to evaluate the efficacy of RSV prefusion vaccine in the prevention of RSV-associated acute respiratory illness. Data from 31,645 vaccinated patients compared with 31,672 controls showed a significant pooled risk reduction in the vaccinated group, with a RR of 0.32 (95% CI: 0.25 to 0.41, I2 = 1%) and an overall vaccine efficacy of 68% (95% CI: 59–75%) (Fig. 3). A total of seven (32%) studies assessing the efficacy of vaccination against medically attended RSV-associated lower respiratory tract illness with data from 35,521 vaccinated versus 35,243 controls showed similarly significant pooled risk reductions in vaccinated groups, with a RR of 0.30 (RR 0.30, 95% CI: 0.23 to 0.40, I2 = 22%). Three (14%) studies reported the lowest RR (RR 0.13, 95% CI: 0.06 to 0.29, I2 = 0%) and minimal heterogeneity in severe RSV-associated lower respiratory tract illness requiring medical attention in the group that received the RSV prefusion F vaccines, with an overall vaccine efficacy of 87% (95% CI: 71–94%). When sensitivity analyses were performed, the heterogeneity of the pooled effects of the results did not change substantially after retaining only subunit vaccines, indicating that our results are robust and reliable.

Fig. 3
figure 3

Vaccine efficacy compared with placebo calculated using the Mantel–Haenszel fixed effects model

Full size image

Immunogenicity of RSV prefusion vaccine

Following the inclusion criteria, 20 studies (91%) on the immunogenicity of RSV prefusion F vaccines were included in this systematic review article (Table 2). There was a significant increase in neutralizing antibody titers against RSV-A in all studies, with a maximum increase of more than 20-fold from baseline. The neutralizing antibody titer against RSV-B was also significantly increased at about one month after immunization, with an increase of more than 1.4-fold compared with baseline. Seven studies examined T cell responses after vaccine immunization simultaneously, and the results showed that mixed adenovirus and subunit vaccine produced the strongest cellular immune responses, with up to 13-fold increase in interferon-γ secretion compared with baseline.

Table 2 Humoral and cellular immune responses following vaccination
Full size table

Safety of RSV prefusion vaccine

The safety profiles of 22 studies were reviewed, and adverse effects of RSV prefusion F vaccination included local reactions such as pain, redness, and swelling at the vaccination site and systemic reactions such as fatigue, headache, Myalgia, joint pain, nausea, and chills (Table 3). The subunit vaccine had the lowest risk of local and systemic adverse reactions, with RR of 2.79 (95% CI: 1.47 to 6.00, I2 = 77%) and 1.24 (95% CI: 0.95 to 1.63, I2 = 74%), respectively, and the risk of serious adverse events (grade ≥ 3) was also the lowest (RR 2.11, 95% CI: 1.41 to 3.15, I2 = 25%) (Fig. 4; Table 3). Redness was the predominant local reaction observed among recipients of the subunit vaccine (RR 4.77, 95% CI: 3.08 to 7.38, I2 = 41%). Conversely, pain at the injection site was the most common local symptom in the mRNA vaccine (RR 40.63, 95% CI: 5.85 to 282.44). Myalgia (RR 3.96, 95% CI: 2.35 to 6.66, I2 = 29%), nausea (RR 3.74, 95% CI: 0.83 to 16.9, I2 = 75%) and chill (RR 7.37, 95% CI: 4.20 to 12.94, I2 = 0%) were the most common symptoms reported in recipients of adenovirus vaccine. Of note, the mRNA vaccine exhibited the highest risk of adverse effects graded as 3 or higher (RR 20.79, 95% CI: 1.30 to 333.14). No RSV prefusion F vaccine-related deaths were recorded in these studies.

Table 3 Incidence of adverse events among the vaccination versus the control group
Full size table
Fig. 4
figure 4

Incidence of grade ≥ 3 adverse events among the vaccination versus the control group

Full size image

Discussion

In this systematic review and meta-analysis of 22 studies, we explore for the first time the efficacy, immunogenicity, and safety of RSV prefusion F vaccine. We found that administration of the RSV prefusion F vaccine significantly reduced the risk of RSV-associated acute respiratory illness, particularly the risk of severe cases of RSV-associated lower respiratory tract illness requiring medical attention. Previous studies have found that vaccines using the fused RSV F protein as antigen, although immunogenic, do not prevent RSV-associated acute respiratory illness in the elderly, and there is no clinically identifiable patient population that may benefit from this vaccine [28]. The failure of these clinical studies has led to intensive investigation of the immune mechanism of RSV. Valuable experience has been accumulated for the development of safe and effective vaccines targeting the F prefusion protein of RSV. In eight studies involving the evaluation of vaccine efficacy, subunit vaccines appeared to provide better protection than adenovirus vaccines, but due to the limited number of studies of the two vaccines included in this study, further research remains imperative.

This study provides a comprehensive assessment of the available literature on RSV prefusion F vaccines. We found that existing subunit vaccines, adenovirus vaccines, mixed subunit and adenovirus vaccines, and mRNA vaccines were able to generate significant immune responses against RSV in vaccine recipients. The titers of neutralizing antibodies against RSV-A and RSV-B and RSV-specific ligation antibodies were significantly different among different vaccine types due to the differences in immunogenicity composition, whether they contained adjuvants or not, immunization dose, immunization times, and detection time. In our study, five studies used the ELISPOT assay to measure T-cell immune responses and showed that subunit vaccines elicited weaker T-cell responses than adenovirus vaccines, mixed subunit and adenovirus vaccines, and mRNA vaccines, which is consistent with the results of a large number of studies of COVID-19 vaccines [29, 30].

Local adverse reactions after vaccination are more common than systemic adverse reactions. For different vaccine types, subunit vaccines are significantly safer and have lower incidence of local and systemic adverse reactions. Consistent with our results, the mRNA vaccine was associated with the highest incidence of adverse reactions except for a few [31]. In addition, mRNA vaccines have a higher association with serious adverse effects than other vaccine types [32]. Myalgia, nausea, and chills were the most common symptoms reported by adenovirus vaccine recipients, findings that were also similar to those previously reported for influenza and COVID-19 vaccines [30]. In theory, these differences could be attributed to differences in the strength of the immune response to the different vaccines [33, 34], as confirmed by the efficacy and immunization results of this review.

In addition, there is concern about whether RSV vaccination can cause a potentially risky rare neurologic disorder (Guillain-Barre syndrome). While GBS is considered uncommon, it remains a significant subject of discussion in the context of vaccination. Previous research on influenza vaccination has reported an eightfold rise in the risk of GBS [35]. Similarly, investigations into COVID-19 vaccines have indicated diverse clinical associations between COVID-19 vaccination and GBS [36, 37]. It is noteworthy that, reassuringly, there is currently no observed elevated risk of GBS associated with RSV vaccination.

This study has several limitations. First, current studies of RSV vaccine protection have been based on assessments of effectiveness during the first RSV season after vaccination (approximately 6 months). There were insufficient data to evaluate the duration of efficacy and immune effects after vaccination, and whether the vaccines result in long-term adverse events, thus necessitating long-term surveillance and study for the population. Second, the study included four vaccine types, but there was considerable variation in the number of studies across vaccine types. To eliminate this effect, we performed a subgroup analysis.

In conclusion, our meta-analysis suggests that vaccines using the RSV prefusion F protein as antigen exhibit favorable efficacy, immunogenicity, and safety in the population. In particular, it provides high protective efficiency against severe RSV-associated lower respiratory tract disease.