Abstract
Respiratory syncytial virus (RSV) antibody durability in immunosuppressed persons following RSV vaccination is unknown. In this observational cohort of immunosuppressed persons, peak responses occurred 1 month after vaccination, without significant waning by 6 months; adjuvanted vaccine recipients had higher responses. This suggests RSV antibody durability of at least 6 months and potential augmentation by adjuvanted vaccine.
Keywords: vaccine, immunocompromised, RSV
Immunosuppressed persons (ISPs) endure a high burden of respiratory syncytial virus (RSV)–related disease, with hospitalization rates of nearly 10% [1]. Given the lack of effective antiviral agents, immunoprophylaxis is the best strategy to prevent RSV-related morbidity in this vulnerable population. Encouragingly, 2 protein-based subunit vaccines containing the prefusion conformation of the RSV fusion protein (preF), RSVpreF3 (Arexvy/RSV-AS01E) and RSVpreF (Abrysvo/RSV-A/B), were licensed and recommended for use in older adults in 2023 [2, 3]. Notably, RSV-AS01E contains an adjuvant, whereas RSV-A/B is unadjuvanted, which might influence immunogenicity and effectiveness in ISPs [4–6]. Regardless, both vaccines are highly efficacious at preventing severe RSV in healthy older adults, though trial data are not available for ISPs. Postlicensure effectiveness data, however, suggest some attenuation in protection against hospitalization compared with healthy individuals, particularly for those with the heaviest immunosuppression, such as bone marrow transplant recipients [7].
Accordingly, we and others have demonstrated attenuated and heterogenous humoral responses to RSV vaccination among ISPs, suggesting that a significant subset of ISPs may not be fully protected, with potential signal for greater short-term neutralization following RSV-AS01E vaccination [4, 8–10]. Furthermore, while these vaccines provide durable protection over ≥2 RSV seasons in healthy older adults, early data in ISPs show negligible effectiveness during a second season, which raises concern for relatively rapid waning of immunity [11]. To better understand the durability of antibody responses to RSV vaccines in ISPs, we used an ongoing national observational cohort to measure longitudinal immune responses, with a focus on potential differences between vaccine platforms.
METHODS
ISPs (solid organ transplant recipients [SOTRs] and/or participants with autoimmune conditions on immunosuppressive medications) were enrolled in a national, prospective, observational cohort of respiratory viral vaccines, as described elsewhere [4]; they were enrolled and consented virtually, with waiver of documentation of consent approved by the Johns Hopkins Institutional Review Board (JHIRB00381814). Participants who reported receiving RSV vaccination in the community between October 2023 and July 2024 submitted longitudinal samples before vaccination and 1, 3, and 6 months after vaccination. Those who received immunoglobulin or plasma products were excluded, and those who submitted ≥2 samples (≥1 before and ≥1 after vaccination) were included (Supplementary Figure 1). Participants in the present study included 38 with previously reported baseline, 1-month, and/or 3-month postvaccine RSV antibody levels [4].
Anti-preF immunoglobulin G (IgG) was measured using an electrochemiluminescent enzyme-linked immunosorbent assay, Respiratory Panel 4 from Meso Scale Diagnostics (MSD), according to the manufacturer's instructions at 1:50 000 dilution. Results were reported in arbitrary units (AU) per milliliter. Plasma neutralization capacity (dilution at which 50% of virus is neutralized or 50% neutralization titer [NT50]) was measured by means of a plaque reduction neutralization titer assay using RSV A2 (NR-12149; BEI Resources, National Institute of Allergy and Infectious Diseases, National Institutes of Health), as described elsewhere [4] (see Supplementary Methods). Seroconversion was defined as a ≥4-fold rise in preF IgG after vaccination, and high-titer neutralization was defined as an NT50 at least as high as the standardized, pre–vaccine era high-titer reference antiserum (NR-4021; BEI Resources) (mean NT50, 2756).
Baseline characteristics of ISPs were recorded and compared between participants who reported vaccination with RSV-AS01E versus RSV-A/B, using Wilcoxon rank sum tests for continuous and Fisher exact tests for categorical variables. The antibody fold rise was calculated as the ratio of postvaccine antibody titers to day 0 titers for each participant at each time point. Differences in preF IgG from day 0 to 1, 3, and 6 months were analyzed by means of Wilcoxon rank sum tests. The proportions of participants who seroconverted or had high titer neutralization at day 0 and at 1, 3, and 6 months were compared using McNemar and Fisher exact testing.
In a post hoc analysis to estimate the changes in preF IgG titers over time, accounting for repeated measures from the same participant, we used a linear mixed effects model. PreF IgG titers were log-transformed and time point, vaccine type, age, mycophenolate mofetil (MMF) exposure, and immunocompromising conditions (SOTR vs other) were included as fixed-effects predictors. A random intercept for each participant was included to account for differences between participants. For additional model details, see the Supplementary Methods. Statistical significance was defined as a 2-sided α value of <.05. Analysis was performed using R (version 4.5.0 or later) and Stata (version 18.0) software.
RESULTS
A total of 47 ISPs provided ≥2 paired samples after RSV vaccination, including 27 who reported receiving RSV-AS01E, 15 who reported RSV-A/B, and 5 who reported an unknown vaccine type (Supplementary Figure 1). The median age of the cohort was 66 years (interquartile range [IQR], 64–73 years), 53% were female, 83% were SOTRs (median time after transplantation, 8 years), and 40% were taking ≥3 immunosuppressive medications. Key clinical and demographic features were similar between vaccine subgroups (Supplementary Table 1). No participants reported an RSV infection during follow-up.
The median preF IgG rose significantly for the whole cohort after vaccination, from 108 501 (IQR, 67 117–174 342) at baseline to a peak of 605 391 (238 548–2 509 723) at 1 month (P < .001); values at 3 months (530 191 [243 748–1 646 151]) and 6 months (570 159 [323 787–2 028 278]) were also significantly higher than at baseline (P < .001). Peak values at 1 month did not differ significantly from those at 6 months (605 391 [238 548–2 509 723] vs 570 159 [323 787–2 028 278]; P > .05) (Supplementary Figure 2A). The preF IgG fold change from baseline was 5.02 (1.63–23.64) at 1 month, 4.10 (2.01–16.87) at 3 months, and 4.94 (1.86–15.42) at 6 months, with 58% (22 of 38), 50% (21 of 42), and 51% (20 of 39) of participants achieving seroconversion at these respective time points. Few participants (n = 3 [6%]) reported taking B-cell–targeted therapies. Specifically, 2 reported rituximab use and demonstrated low day 30 antibodies (10th–25th percentile) while 1 reported belimumab use, with high day 30 antibodies (97th percentile). Overall inferences were similar when including versus excluding these participants (data not shown).
Fold rises did not differ significantly between any of the postvaccine time points (P > .05) (Supplementary Figure 2B). Similarly, median NT50 values rose from 444 (IQR, 250–770) at baseline to a peak of 2978 (723–8525) at 1 month (P < .001); the values at 3 months (1953 [769–5799]) and 6 months (1566 [554–8137]) were also significantly higher than at baseline (P < .001). Peak titers at 1 month did not differ significantly from 6-month titers (2978 [723–8525] vs 1566 [554–8137], respectively; P = .14) (Supplementary Figure 2C). The proportions with high-titer responses were 53% (20 of 38), 43% (18 of 42), and 41% (16 of 39) at 1, 3, and 6 months after vaccination; the proportions at 1 versus 6 months did not differ significantly (P = .37; McNemar test).
Comparing responses between the RSV-AS01E and RSV-A/B vaccines, preF IgG levels were significantly higher among RSV-AS01E recipients at 1 month (median [IQR], 1 905 705 [368 400–2 852 324] vs 300 934 [180 647–518 074], respectively; P = .03), 3 months (1 419 272 [353 642–3 338 287] vs 320 400 [150 961–464 170]; P = .01), and 6 months (570 159 [365 243–3 058 605] vs 325 114 [284 268–589 409]; P = .04) (Figure1A).
Figure 1.
Longitudinal respiratory syncytial virus (RSV) antibodies after RSV vaccination. A, Anti–prefusion conformation of the RSV fusion protein (preF) immunoglobulin (Ig) G over time. Abbreviation: AU, arbitrary units. B, Box plots showing 50% neutralization titer (NT50) over time. Dots represent individual antibody values at baseline and postvaccination time points; horizontal black lines within box plots, median values; and boxes, interquartile ranges (IQRs), with upper edges representing the third quartile (Q3), lower edges the first quartile (Q1), and whiskers extending to 1.5 times Q3 and Q1. The horizontal orange line in B represents high-titer neutralization, corresponding to high-titer polyclonal pre–vaccine era reference serum (NR-4021; BEI Resources) (NT50, 2756). Percentages listed represent the proportion of values above the high-titer line for each vaccine group. P values above the boxes represent comparisons of absolute IgG or NT50 values between vaccine types, using Wilcoxon rank sum tests; P values below the boxes, comparisons of the proportions above the high-titer mark between vaccine types, using Fisher exact tests.
The proportion of participants achieving seroconversion was higher in RSV-AS01E than in RSV-A/B recipients at all time points, particularly at 3 and 6 months after vaccination (67% vs 36%, respectively, at 1 month [P = .09], 64% vs 15% [P = .006] at 3 months, and 62% vs 23% at 6 months [P = .03]) (Supplementary Figure 3). NT50 values were also higher at all time points in RSV-AS01E than in RSV-A/B recipients, with differences reaching statistical significance at 3 months (median [IQR], 4408 [1113–8525] vs 1714 [676–2470], respectively, at 1 month [P = .24], 4201 [1149–8249] vs 1126 [639–2780] at 3 months [P = .03], and 3089 [530–8210] vs 1164 [554–1922] [P = .43] at 6 months) (Figure1B). The proportion of participants with high-titer neutralization was also greater in RSV-AS01E than in RSV-A/B recipients, particularly at 1 month after vaccination (67% vs 21%, respectively, at 1 month [P = .01], 52% vs 31% [P = .31] at 3 months, and 52% vs 23% [P = .15] at 6 months). There were no significant differences between participants who did and those who did not achieve high-titer neutralization at any time point, though numerically more kidney transplant recipients did not achieve a high-titer response (P = .08; Table 1).
Table 1.
Characteristics of Participants by 50% Neutralization Titer Responses
| Characteristic | Participants, No. (%)a | P Value | |
|---|---|---|---|
| High Titer (n = 23) | Low Titer (n = 19) | ||
| Age, median (IQR), y | 66 (64–71) | 68 (63–75) | .60 |
| Female | 13 (57) | 9 (47) | .76 |
| Transplant type | |||
| Kidney | 10 (50) | 12 (80) | .08 |
| Liver | 6 (30) | 2 (13) | .42 |
| Heart | 2 (10) | 1 (7) | >.9 |
| Lung | 2 (10) | 0 (0) | .50 |
| Autoimmune conditions | |||
| Rheumatoid arthritis | 1 (33) | 1 (25) | >.9 |
| Systemic lupus erythematosus | 1 (33) | 2 (50) | >.9 |
| Other | 1 (33) | 1 (25) | >.9 |
| Time since transplant, median (IQR), y | 7 (6–12) | 9 (5–17) | |
| Immunosuppressive medications | |||
| Calcineurin inhibitor | 18 (78) | 15 (79) | >.9 |
| Glucocorticoid | 8 (35) | 9 (47) | .53 |
| Mycophenolate | 11 (48) | 11 (58) | .55 |
| mTOR inhibitor | 5 (22) | 1 (5) | .20 |
| Biologic | 2 (9) | 1 (5) | >.9 |
| Vaccine received | |||
| RSV-AS01E | 17 (74) | 10 (53) | .20 |
| RSV-A/B | 6 (26) | 9 (47) | |
| ≥3 Immunosuppressive medications | 8 (35) | 9 (47) | .53 |
| Vaccine coadministration | 13 (57) | 8 (42) | .54 |
Abbreviations: IQR, interquartile range; mTOR, mammalian target of rapamycin; RSV, respiratory syncytial virus.
aData represent no. (%) of participants unless otherwise specified.
In adjusted mixed effects linear regression modeling, preF IgG titers rose approximately 1.8 log10 AU/mL by 1 month and remained stable for up to 6 months. Receipt of the unadjuvanted RSV-A/B (β = −.61 [−1.18 to −.02]; P = .03) and MMF exposure (β = −.81 [−1.4 to −.18]; P = .01) were significantly negatively associated with the preF IgG response (Supplementary Figure 4A and Supplementary Table 2A). When MMF exposure was stratified by dose, high-dose MMF (>1000 mg/d) was significantly negatively associated with preF IgG levels (Supplementary Table 3). There was a statistically significant interaction between vaccine type and MMF exposure, namely, in participants not taking MMF, vaccination with RSV-AS01E (vs RSV-A/B) was associated with a greater increase in preF IgG (β = 1.26 [.06–2.47]; P = .04) (Supplementary Figure 4B and Supplementary Table 2B).
DISCUSSION
In this first report of longer-term antibody responses to RSV vaccination in ISPs, we found relatively preserved binding and neutralizing responses following a single dose of protein-based vaccine through 6 months. This contrasts with more rapid waning noted following messenger RNA coronavirus disease 2019 and influenza vaccines and supports the potential for longer duration of protection against RSV [12, 13]. However, the data also redemonstrate heterogeneity and attenuated antibody responses across the immunosuppressed population, which differs from universal strong response in healthy study participants [14]. Specifically, >40% of ISPs never achieved neutralizing antibody levels above a conservative threshold of unvaccinated control plasma. Moreover, fold increases in the present study peaked at a median of 5 compared with >10 in prior studies of healthy participants [2]. In addition to lower antibody levels in those taking MMF-based immunosuppression, a finding consistent with response to other vaccines, receipt of the adjuvanted RSV-AS01E vaccine was associated with higher preF and NT50 values in both the primary analysis and mixed-effects modeling [6, 15]. This is consistent with work in influenza vaccines that demonstrated improved immunogenicity with an adjuvanted vaccine over a standard unadjuvanted dose in ISPs [5]. Interestingly, this augmentation of response by adjuvanted RSV vaccination appeared muted in those taking MMF, signifying that additional approaches to RSV vaccination or prevention, such as multidose vaccination or passive immunoprophylaxis, may be necessary in this subgroup.
The current study was limited by its observational nature, its lack of nonimmunosuppressed controls, and its relatively small sample with a high proportion of kidney transplant recipients, which may limit generalizability to all SOTRs or other immunosuppressed groups. In addition, cellular immunity and other mechanisms of immunoprotection were not explored. However, this study does provide evidence that 6-month RSV vaccine responses among ISPs are not uniform and appear to vary by vaccine platform and immunosuppressive regimen. This reinforces the need to work toward more personalized RSV vaccine recommendations among immunocompromised patients, including direct comparison of platforms in this group. Ongoing studies are investigating alternative RSV vaccine approaches, including 2-dose and booster-dose series [16, 17].
Supplementary Material
Notes
Acknowledgments. The authors thank the participants of the Emerging Pathogens of Concern study, without whom this research could not be possible. They also thank the members of the Transplant Research Center at Johns Hopkins and the members of the Viral Immunity and Pathogenesis Center at Johns Hopkins.
Author contributions. W. A. W. and A. H. K. conceived of and designed the study and acquired funding. Z. N., M. R., and C. H. performed the analysis. M. C., X. G., W. G., and Y. E. performed data curation and study management. P. B., S. A., and I. S. performed the assays. A. A. R. T., W. A. W. , and A. H. K. provided supervision. Z. N., W. A. W., and A. H. K., wrote the original draft. All authors contributed to editing the manuscript.
Data availability statement. Reasonable requests to the corresponding author for deidentified data will be granted.
Financial support. This work was supported by the National Institute of Allergy and Infectious Diseases (grants K08AI156021 and R01AI190195 to A. H. K. and grants K23AI157893 and R01AI190359 to W. A. W.) and the Willowcroft Foundation (support to A. H. K.).
Contributor Information
Zeba Nauroz, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Prasanthy Balasubramanian, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Moreno Rodrigues, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Shreya Arondekar, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Isabella Sengsouk, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Camille Hage, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Maggie Chahoud, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Xori Green, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Woudase Gallo, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Yolanda Eby, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Aaron A R Tobian, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
William A Werbel, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Andrew H Karaba, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Supplementary Data
Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
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