≪詳細版≫４.シリーズ:妊婦へのRSVワクチンは危険 (1)試験の割付不公平では

Dear Editor
　　Concerns have been raised regarding informed consent for pregnant women in Pfizer’s RSV vaccine trial [1] and questions have been asked as to why one of two similar RSV vaccines was associated with adverse outcomes – namely increased preterm birth and neonatal death ― while the other was not [2].

　　Here, we discuss another concern relating to Pfizer’s RSV vaccine (Abrysvo) trials that may be related to these issues.

　　The Abrysvo trials [3-6] were all placebo-controlled randomized-controlled trials (RCTs). This assumes fair allocation between vaccine and placebo groups.

　　However, in the phase 3 trial [3-5], there may have been an imbalance in randomization. Congenital abnormalities would neither increase nor decrease when a pregnant woman receives a substance that does not cause such abnormalities; rather, they should occur at similar rates in both groups. Conversely, if a substance inhibits fetal development, an increase in congenital abnormalities would occur more frequently in the vaccine group than in the placebo group.

　　However, significantly fewer serious congenital abnormalities were reported in the Abrysvo group than in the placebo group. In the interim report [3], the proportion was 4.3% (152/3568) in the vaccine group and 5.3% (189/3558) in the placebo group, with an odds ratio of 0.79 (95% CI: 0.64, 0.99), p=0.038 [6].

　　Such bias could occur if mothers in the placebo group were more frequently exposed to external risk factors known to increase congenital anomalies, such as anticonvulsants, benzodiazepines, antidepressants, alcohol, smoking, other addictive substances, radiation, or certain infectious diseases (e.g., rubella, but not RSV infection).. Therefore, histories of such exposures should be included as baseline characteristics. According to the protocol [3], maternal substance use and obstetric history were collected. However, published reports of both the phase 3 trial [3-5] and the phase 2 trial [7] included only maternal age, gestational age at vaccination, and race as baseline characteristics. In the phase 2 trial, the proportion of congenital anomalies was non-significantly higher (21.5%=17/79) in the Abrysvo groups than in the placebo group (11.5%=9/78), with an odds ratio of 2.10 (95% CI: 0.87, 5.06, p=0.093),. The marked discrepancy between the phase 2 and phase 3 results further raises concerns regarding the adequacy of randomization in the phase 3 trial.

　　Moreover, the reported congenital anomaly rates ―5.7% in the phase 3 placebo group [3], 21.5% in the phase 2 for Abrysvo group, and 11.5% in the phase 2 placebo group [7]― are considerably higher than the generally reported prevalence of 3-4% among newborns. Maternal substance use history, particularly the use of hypnotics, antianxiety medications, antidepressants, anticonvulsants, and addictive substances, should be disclosed as essential baseline characteristics that can cause congenital anomalies.

　　Turning to mortality, gestational age at delivery is one of the major determinants of neonatal survival and morbidity [8]. In the GSK’s similar vaccine trial, both the risk of preterm births and neonatal deaths increased [2]. In contrast, in the Abrysvo trial, while preterm birth increased, the neonatal death decreased. The total number of non-RSV-related death was only about half in the placebo group: 5 vs 11 in the interim report [3], and 8 vs 13 in the final report [4]. If imbalances in maternal substance use existed between groups, such differences could affect not only congenital anomalies but also mortality, and it could have a significant impact on the incidence of various other adverse events.

　　For these reasons, substance use histories should be disclosed for the Abrysvo trials.

References
1) Boytchev H. Concerns over informed consent for pregnant women in Pfizer’s RSV vaccine trial BMJ 2023 Nov 15;383:p2620 doi: https://doi.org/10.1136/bmj.p2620, PMID: 37967888
2) Boytchev H. Maternal RSV vaccine: Further analysis is urged on preterm births BMJ 2023 10 May 2023;381:p1021 doi: https://doi.org/10.1136/bmj.p1021
3) Kampmann B, Madhi SA, Munjal I, et al. Bivalent Prefusion F Vaccine in Pregnancy to Prevent RSV Illness in Infants. NEJM. 2023; 388: 1451-1464. PMID: 37018474. (with protocol and supplementary appendix)
4) Madhi SA, Kampmann B, Simoes EAF, et al. Preterm Birth Frequency and Associated Outcomes From the MATISSE (Maternal Immunization Study for Safety and Efficacy) Maternal Trial of the Bivalent Respiratory Syncytial Virus Prefusion F Protein Vaccine Obstet Gynecol 2025; 145: 147-156. PMID: 39746206 (with supplementary appendix).
5) Simoes EAF, Pahud BA, Madhi SA, et al. Efficacy, Safety, and Immunogenicity of the MATISSE (Maternal Immunization Study for Safety and Efficacy) Maternal Respiratory Syncytial Virus Prefusion F Protein Vaccine Trial. Obstet Gynecol 2025; 145: 157-167. PMID: 39746212 (with supplementary appendix).
6) MedCheck Editorial Team. Respiratory Syncytial Virus Vaccine (Abrysvo®) Harms, suspected false-negatives and allocation bias. MedCheck in English 2025: 11(32): 4-11. https://medcheckjp.org/wp-content/uploads/2025/04/Eng-no-32.pdf
7) Simoes EAF, Center KJ, Tita ATN, et al. Prefusion F Protein-Based Respiratory Syncytial Virus Immunization in Pregnancy. NEJM. 2022; 386: 1615-1626. PMID: 35476650.
8) Manuck TA, Rice MM, Bailit JL et al. Preterm neonatal morbidity and mortality by gestational age: a contemporary cohort. Am J Obstet Gynecol. 2016 Jul;215(1):103.e1-103.e14. doi: 10.1016/j.ajog.2016.01.004. Epub 2016 Jan 7.PMID: 26772790

Competing interests: No competing interests

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