Three Dose Levels of a Maternal Respiratory Syncytial Virus Vaccine Candidate Are Well Tolerated and Immunogenic in a Randomized Trial in Nonpregnant Women

Tino F Schwarz, Casey Johnson, Christine Grigat, Dan Apter, Peter Csonka, Niklas Lindblad, Thi Lien-Anh Nguyen, Feng F Gao, Hui Qian, Antonella N Tullio, Ilse Dieussaert, Marta Picciolato, Ouzama Henry, Tino F Schwarz, Casey Johnson, Christine Grigat, Dan Apter, Peter Csonka, Niklas Lindblad, Thi Lien-Anh Nguyen, Feng F Gao, Hui Qian, Antonella N Tullio, Ilse Dieussaert, Marta Picciolato, Ouzama Henry

Abstract

Background: Respiratory syncytial virus (RSV) causes respiratory tract infections, which may require hospitalization especially in early infancy. Transplacental transfer of RSV antibodies could confer protection to infants in their first months of life.

Methods: In this first-in-human, placebo-controlled study, 502 healthy nonpregnant women were randomized 1:1:1:1 to receive a single dose of unadjuvanted vaccine containing 30/60/120 µg of RSV fusion (F) protein stabilized in the prefusion conformation (RSVPreF3) or placebo.

Results: Solicited local adverse events (AEs) were more frequently reported in the RSVPreF3 groups (4%-53.2%) versus placebo (0%-15.9%); most were mild/moderate. Unsolicited AEs were comparably reported among groups. Three serious AEs were reported; none was vaccination-related. Compared with prevaccination values, anti-RSV A neutralizing antibody geometric mean titers and anti-RSVPreF3 immunoglobulin G geometric mean concentrations increased 8- to 14-fold and 12- to 21-fold at day 8 and persisted 5- to 6-fold and 6- to 8-fold higher until day 91 in the RSVPreF3 groups versus 1-fold in placebo. Comparisons at day 8 and day 31 showed that the higher dose levels were significantly more immunogenic than the lowest one.

Conclusions: The RSVPreF3 vaccine was well tolerated and immunogenic. The 60 and 120 µg dose levels were selected for further investigation in pregnant women.

Clinical trials registration: NCT03674177.

Keywords: RSV; RSV vaccine; immunogenicity; maternal vaccine; nonpregnant women; respiratory syncytial virus; safety; vaccination.

© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.
Figure 1.
Plain language summary.
Figure 2.
Figure 2.
Participant flow chart. Abbreviations: 30 RSVPreF3/60 RSVPreF3/120 RSVPreF3, group receiving 1 dose of the RSV vaccine containing 30, 60, or 120 µg of RSVPreF3 antigen; D, day; n, number of women; placebo, group receiving 1 dose of placebo; RSV, respiratory syncytial virus.
Figure 3.
Figure 3.
Incidence of solicited local and general adverse events from day 1 to day 7 postvaccination (exposed set). Error bars indicate 95% confidence intervals. Abbreviations: 30 RSVPreF3/60 RSVPreF3/120 RSVPreF3, group receiving 1 dose of the RSV vaccine containing 30, 60, or 120 µg of RSVPreF3 antigen; GI, gastrointestinal; placebo, group receiving 1 dose of placebo; RSV, respiratory syncytial virus.
Figure 4.
Figure 4.
Anti-RSV A neutralizing antibody geometric mean titers (neutralization assay [ED60]; per protocol set). Error bars indicate 95% confidence intervals. Abbreviations: 30 RSVPreF3/60 RSVPreF3/120 RSVPreF3, group receiving 1 dose of the RSV vaccine containing 30, 60, or 120 µg of RSVPreF3 antigen; ED60, serum dilution inducing 60% reduction in plaque-forming units; GMTs, geometric mean titers; placebo, group receiving 1 dose of placebo; RSV, respiratory syncytial virus.
Figure 5.
Figure 5.
Anti-RSVPreF3 IgG antibody geometric mean concentrations (enzyme-linked immunosorbent assay [EU/mL]; per protocol set). Error bars indicate 95% confidence intervals. Abbreviations: 30 RSVPreF3/60 RSVPreF3/120 RSVPreF3, group receiving 1 dose of the RSV vaccine containing 30, 60, or 120 µg of RSVPreF3 antigen; EU, laboratory units of enzyme-linked immunosorbent assay; GMCs, geometric mean concentrations; IgG, immunoglobulin G; placebo, group receiving 1 dose of placebo; RSV, respiratory syncytial virus.

References

    1. Shi T, McAllister DA, O’Brien KL, et al. ; RSV Global Epidemiology Network . Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study. Lancet 2017; 390:946–58.
    1. Stein RT, Bont LJ, Zar H, et al. . Respiratory syncytial virus hospitalization and mortality: systematic review and meta-analysis. Pediatr Pulmonol 2017; 52:556–69.
    1. Nair H, Nokes DJ, Gessner BD, et al. . Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis. Lancet 2010; 375:1545–55.
    1. Jorquera PA, Tripp RA. Respiratory syncytial virus: prospects for new and emerging therapeutics. Expert Rev Respir Med 2017; 11:609–15.
    1. American Academy of Pediatrics. Updated guidance for palivizumab prophylaxis among infants and young children at increased risk of hospitalization for respiratory syncytial virus infection. Pediatrics 2014; 134:e620–38.
    1. Sun Z, Pan Y, Jiang S, Lu L. Respiratory syncytial virus entry inhibitors targeting the F protein. Viruses 2013; 5:211–25.
    1. American Academy of Pediatrics. Diagnosis and management of bronchiolitis. Pediatrics 2006; 118:1774–93.
    1. Munoz FM, Jamieson DJ. Maternal immunization. Obstet Gynecol 2019; 133:739–53.
    1. Vojtek I, Dieussaert I, Doherty TM, et al. . Maternal immunization: where are we now and how to move forward? Ann Med 2018; 50:193–208.
    1. Anderson LJ, Dormitzer PR, Nokes DJ, Rappuoli R, Roca A, Graham BS. Strategic priorities for respiratory syncytial virus (RSV) vaccine development. Vaccine 2013; 31 (Suppl 2):B209–15.
    1. Munoz FM, Piedra PA, Glezen WP. Safety and immunogenicity of respiratory syncytial virus purified fusion protein-2 vaccine in pregnant women. Vaccine 2003; 21:3465–7.
    1. Muňoz FM, Swamy GK, Hickman SP, et al. . Safety and immunogenicity of a respiratory syncytial virus fusion (F) protein nanoparticle vaccine in healthy third-trimester pregnant women and their infants. J Infect Dis 2019; 220:1802–15.
    1. Madhi SA, Polack FP, Piedra PA, et al. ; Prepare Study Group . Respiratory syncytial virus vaccination during pregnancy and effects in infants. N Engl J Med 2020; 383:426–39.
    1. McLellan JS, Ray WC, Peeples ME. Structure and function of respiratory syncytial virus surface glycoproteins. In: Anderson JL, Graham SB, eds. Challenges and opportunities for respiratory syncytial virus vaccines. Berlin, Heidelberg: Springer, 2013:83–104.
    1. Kwakkenbos MJ, Diehl SA, Yasuda E, et al. . Generation of stable monoclonal antibody-producing B cell receptor-positive human memory B cells by genetic programming. Nat Med 2010; 16:123–8.
    1. Ngwuta JO, Chen M, Modjarrad K, et al. . Prefusion F-specific antibodies determine the magnitude of RSV neutralizing activity in human sera. Sci Transl Med 2015; 7:309ra162.
    1. Crank MC, Ruckwardt TJ, Chen M, et al. ; VRC 317 Study Team . A proof of concept for structure-based vaccine design targeting RSV in humans. Science 2019; 365:505–9.
    1. McLellan JS, Chen M, Joyce MG, et al. . Structure-based design of a fusion glycoprotein vaccine for respiratory syncytial virus. Science 2013; 342:592–8.
    1. Graham BS, Modjarrad K, McLellan JS. Novel antigens for RSV vaccines. Curr Opin Immunol 2015; 35:30–8.
    1. Food and Drug Administration. Guidance for industry: toxicity grading scale for healthy adult and adolescent volunteers enrolled in preventive vaccine clinical trials. 2007.
    1. Graham JM Jr. Update on the gestational effects of maternal hyperthermia. Birth Defects Res 2020; 112:943–52.
    1. Dreier JW, Andersen AM, Berg-Beckhoff G. Systematic review and meta-analyses: fever in pregnancy and health impacts in the offspring. Pediatrics 2014; 133:e674–88.
    1. Shi QY, Zhang JB, Mi YQ, Song Y, Ma J, Zhang YL. Congenital heart defects and maternal fever: systematic review and meta-analysis. J Perinatol 2014; 34:677–82.
    1. Moretti ME, Bar-Oz B, Fried S, Koren G. Maternal hyperthermia and the risk for neural tube defects in offspring: systematic review and meta-analysis. Epidemiology 2005; 16:216–9.
    1. Pichichero ME. Challenges in vaccination of neonates, infants and young children. Vaccine 2014; 32:3886–94.
    1. Buchwald AG, Graham BS, Traore A, et al. . RSV neutralizing antibodies at birth predict protection from RSV illness in infants in the first three months of life [published online ahead of print 28 May 2020]. Clin Infect Dis doi: 10.1093/cid/ciaa648.
    1. Chu HY, Steinhoff MC, Magaret A, et al. . Respiratory syncytial virus transplacental antibody transfer and kinetics in mother-infant pairs in Bangladesh. J Infect Dis 2014; 210:1582–9.
    1. Eick A, Karron R, Shaw J, et al. . The role of neutralizing antibodies in protection of American Indian infants against respiratory syncytial virus disease. Pediatr Infect Dis J 2008; 27:207–12.
    1. Ochola R, Sande C, Fegan G, et al. . The level and duration of RSV-specific maternal IgG in infants in Kilifi Kenya. PLoS One 2009; 4:e8088.
    1. Stensballe LG, Ravn H, Kristensen K, et al. . Respiratory syncytial virus neutralizing antibodies in cord blood, respiratory syncytial virus hospitalization, and recurrent wheeze. J Allergy Clin Immunol 2009; 123:398–403.
    1. Kaaijk P, Luytjes W, Rots NY. Vaccination against RSV: is maternal vaccination a good alternative to other approaches? Hum Vaccin Immunother 2013; 9:1263–7.
    1. Munoz FM. Respiratory syncytial virus in infants: is maternal vaccination a realistic strategy? Curr Opin Infect Dis 2015; 28:221–4.
    1. Abu Raya B, Srugo I, Kessel A, et al. . The effect of timing of maternal tetanus, diphtheria, and acellular pertussis (Tdap) immunization during pregnancy on newborn pertussis antibody levels—a prospective study. Vaccine 2014; 32:5787–93.
    1. Chu HY, Englund JA. Maternal immunization. Clin Infect Dis 2014; 59:560–8.
    1. Eberhardt CS, Blanchard-Rohner G, Lemaître B, et al. . Maternal immunization earlier in pregnancy maximizes antibody transfer and expected infant seropositivity against pertussis. Clin Infect Dis 2016; 62:829–36.
    1. Eberhardt CS, Blanchard-Rohner G, Lemaître B, et al. . Pertussis antibody transfer to preterm neonates after second- versus third-trimester maternal immunization. Clin Infect Dis 2017; 64:1129–32.
    1. Zhong Z, Haltalli M, Holder B, et al. . The impact of timing of maternal influenza immunization on infant antibody levels at birth. Clin Exp Immunol 2019; 195:139–52.
    1. Beran J, Lickliter JD, Schwarz TF, et al. . Safety and immunogenicity of 3 formulations of an investigational respiratory syncytial virus vaccine in nonpregnant women: results from 2 phase 2 trials. J Infect Dis 2018; 217:1616–25.
    1. Langley JM, Aggarwal N, Toma A, et al. . A randomized, controlled, observer-blinded phase 1 study of the safety and immunogenicity of a respiratory syncytial virus vaccine with or without alum adjuvant. J Infect Dis 2017; 215:24–33.
    1. Schwarz T, Johnson C, Grigat C, et al. . Different dose levels of a respiratory syncytial virus maternal vaccine candidate (RSVPreF3) administered to non-pregnant women in a randomized clinical trial are immunogenic and well tolerated. Open Forum Infect Dis 2020; 7(Suppl 1):S638–9.

Source: PubMed

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