Comparison between the safety of the HPV vaccine versus placebo: a systematic review and meta-analysis of randomized clinical trials

Santos, Swelen Aparecida dos; Sato, Mariane Yoshie; Basilio, Pedro Henrique Gunha; Pereira, Meire Ellen; Julião, Rafaela Climaco; Arruda, Nielson da Cunha; Silva, Davi Paula da; Oliveira, Cláudia Sirlene; Costa-Junior, Victor Horacio de Souza; Guiloski, Izonete Cristina

doi:10.1016/j.jped.2025.04.009

home Sumário navigate_before Anterior Atual Seguinte navigate_next

home Sumário

Review articles • J. Pediatr. (Rio J.) 101 (5) • 2025 • https://doi.org/10.1016/j.jped.2025.04.009 linkcopy

Comparison between the safety of the HPV vaccine versus placebo: a systematic review and meta-analysis of randomized clinical trials

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Objective Human Papillomavirus (HPV) is a virus that targets epithelial tissues. Virtually all cases of cervical cancer are related to HPV, emphasizing the importance of vaccines in prevention. Although >200 million doses have been administered worldwide, concerns persist about adverse reactions. This study evaluated the safety of the HPV vaccine and the main adverse effects.

Data sources The study was registered in the PROSPERO database (CRD42023365692). The systematic searches were conducted in the PubMed, Scopus, Embase, Cochrane, Science Direct, and Web of Science databases using the search strategy "HPV" AND "vaccine" AND "safety" NOT "COVID" from 01/01/2007 to 31/12/2022. Inclusion criteria were based on the PICOT strategy, focusing on studies with humans, vaccinated populations comprising children, adolescents, and adults, and Phase II/III randomized clinical trials. The PEDro scale was used to assess the quality of the studies.

Summary of findings Eleven articles were qualified for qualitative synthesis and meta-analysis. The results indicated that HPV vaccination was associated with increased local reactions, fatigue, and myalgia compared to the placebo. However, there were no significant differences in serious adverse events, gastrointestinal reactions, cutaneous effects, headache, or fever between the vaccine and placebo groups.

Conclusion Local reactions, fatigue, and myalgia were more prevalent in the HPV vaccine group; the overall safety profile of the vaccine was favorable. The HPV vaccine was deemed safe, mirroring the profile of adverse reactions seen with other vaccines. With its potential to prevent cancer, the benefits of HPV vaccination far outweigh the minimal risks.

Keywords
Papillomavirus infections; Immunization; Uterine cervical neoplasms

Reference	Country	Participants characteristics Sex/Agea (n)	Vaccine/ Number of doses/ Application rangeb	Results
Chen et al.¹⁵	China	Females 20-45 (1499)	Quadrivalent Gardasil 3 doses 0-2-6	Four participants (two in the qHPV vaccine and two in the placebo) discontinued the study vaccination due to adverse effects (AEs) that were considered vaccination-related. Within 15 days following any vaccination, injection-site AEs were more frequent among qHPV vaccine recipients, and systemic AEs were similar in frequency between the qHPV vaccine and placebo groups.
Kim et al.³⁷	South Korea	Females 15-25 (140)	Bivalent Cervarix 3 doses 0-1-6	Local (pain) and general (fatigue, myalgia, or headache) symptoms were commonly reported in both groups.
Li et al.¹⁹	China	Males 9-15 (100) Females 9-45 (500)	Quadrivalent Gardasil 3 doses 0-2-6	The qHPV vaccine was generally well tolerated. Injection site AEs were higher in vaccine than placebo recipients. Vaccine-related systemic AEs were reported with similar frequency in vaccine and placebo recipients. There was one serious AE among placebo recipients that was determined by the investigator to be not related to vaccination.
Mikamo et al.¹¹	Japan	Males 16-26 (554)	Quadrivalent Gardasil 3 doses 0-2-6	Vaccination-related AEs were slightly higher in the qHPV vaccine than in the placebo group. The most common reactions were mild to moderate injection site pain, erythema, and swelling.
Moreira et al.¹⁶	Australia Canada Colombia Denmark Hong Kong Mexico Sweden United States	Females 12-26 (608)	Nonavalent Gardasil 3 doses 0-2-6	The most common AEs were injection-site events, the majority of which were mild. Overall, the 9vHPV vaccine was generally well tolerated in prior qHPV vaccine recipients.
Mugo et al.²¹	Ghana Kenya Senegal	Females 9-26 (227)	Quadrivalent Gardasil 3 doses 0-2-6	Across vaccination groups, the most common AEs were at the injection site, including pain, swelling, and erythema. No subject discontinued study medication due to an AE and no serious AEs were reported. There were no deaths. This study demonstrated that qHPV vaccination of Sub-Saharan African women was highly immunogenic and generally well tolerated.
Muñoz et al.³⁸	Colombia France Germany Philippines Spain Thailand United States	Females 24-45 (1908)	Quadrivalent Gardasil 3 doses 1-2-6	The proportion of women who reported a serious AE on days 1-15 after any vaccination was comparable between the vaccine and placebo groups. Injection-site AEs were mainly responsible for the slight increase in AEs recorded in the vaccine group. There were no vaccine-related serious AEs recorded.
Reisinger et al.²²	North and Latin America Europe Asia	Males and Females 9-15 (1165)	Quadrivalent Gardasil 3 doses 0-2-6	A higher proportion of vaccine recipients than placebo recipients reported one or more injection-site AEs following any vaccination. Rates of fever were similar between vaccination groups. No serious vaccine-related adverse experiences were reported.
Sow et al.¹⁸	Sub-Saharan Africa	Females 10-25 (450)	Bivalent Cervarix 3 doses 0-1-6	Injection site pain was the most frequent local symptom in both groups. Local reactions were higher among the vaccine group. The most frequently observed general symptoms in both groups were headache and fever. No participant withdrew owing to AEs. No vaccine-related serious adverse events were reported.
Zhu et al.¹⁷	China	Females 18-25 (3026)	Bivalent Cervarix 3 doses 0-1-6	Symptoms were generally mild, self-limiting, and of short duration. Injection site symptoms (pain, redness, and swelling) were reported in a numerically higher percentage of subjects in the vaccine group than in the control group. One serious adverse effect (gastrointestinal tract infection) was assessed by the investigator as possibly related to vaccination. Safety outcomes between groups were generally similar.
Zhu et al.²⁰	China	Females 9-45 (374)	Bivalent Cervarix 3 doses 0-1-6	The 2vHPV had an acceptable safety profile when administered to healthy Chinese females. The incidence of solicited local symptoms following any dose was generally higher in the vaccine group than in the control group. None of the serious AEs was considered to have a causal relationship to vaccination by the investigator, and no event had a fatal outcome.

vertical_align_top show_chart

more_horiz close
- image
- translate
- link
- article
- vertical_align_top
- file_download
- show_chart
- image
- translate
- link
- article

location_on

Sociedade Brasileira de Pediatria Av. Carlos Gomes, 328 cj. 304, CEP: 90480-000 , Tel.: (+55 51) 3108-3328 - Porto Alegre - RS - Brazil
E-mail: jped2@sbp.com.br

rss_feed Acompanhe os números deste periódico no seu leitor de RSS

[1] AEs, adverse effects; HIV, Human immunodeficiency virus; HPV, Human papillomavirus; qHPV, quadrivalent vaccine; 2vHPV, bivalent vaccine; 9vHPV, nonavalent vaccine

[TFN1] ^a
years.

[TFN2] ^b
months.