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ESCUDDO Efficacy Trial

Scientific Evaluation of One or Two Doses of the Bivalent or Nonavalent Prophylactic HPV Vaccines

ESCUDDO: Estudio de Comparacion de Una y Dos Dosis de Vacunas Contra el Virus de Papiloma Humano (VPH)

Vaccines that protect against human papillomavirus (HPV) infection can substantially reduce the risk of cervical cancer, and other cancers attributable to HPV. However, HPV vaccination rates are too low, especially in countries and regions with very high rates of cervical cancer and low resources. These vaccines are expensive and giving multiple doses can be difficult, especially in low-resource settings. Researchers from DCEG and Costa Rica are conducting the ESCUDDO study in order to determine if one dose of the HPV vaccines works as well as two doses in young women.

Public Health Impact

ESCUDDO is part of the Cancer Moonshot Initiative. Findings from the trial will provide the definitive evidence of the non-inferiority of one dose compared to two doses, which was the global gold standard in young girls until late 2022, when the WHO provided an alternative, off-label recommendation for providing two or one doses.

If one dose of an HPV vaccine were found to be sufficient to prevent HPV infections, which would reduce cervical precancer and cancer rates and burden, we would expect more widespread vaccine uptake. This could impact the United States and the world, with vaccination programs being able use existing resources to vaccinate more individuals. 

Background and Study Rationale

The impetus for this trial came from a discovery in the NCI Costa Rica Vaccine Trial (CVT), a phase-III efficacy trial launched in 2004. DCEG and Costa Rica investigators, in post hoc analyses, reported that one or two doses of the ASO-4 adjuvanted HPV vaccine may be sufficiently efficacious and that antibody titers remained elevated for years after a single vaccine dose. The latter finding was particularly novel and unexpected, given that previous subunit vaccines typically required at least two doses (prime/boost regimen) to induce lasting responses. These observations raised the possibility that a single dose of HPV vaccine may offer sufficient durable protection and set the basis for ESCUDDO (efficacy trial), and two additional clinical trials conducted by NCI and ACIB-FUNIN—PRIMAVERA (immunobridging trial, Clinical trials identifier: NCT03728881) and PRISMA (efficacy trial, Clinical trials identifier: NCT05237947). 

This research question is also being investigated in other trials, including the DoRIS trial in Tanzania (immunogenicity trial, the ‘sister study’ to the ESCUDDO trial, Clinical trials identifier: NCT02834637), the KenSHE trial in Kenya (efficacy trial, Clinical trials identifier: NCT03675256), and the HANDS HPV trial in the Gambia (immunogenicity trial, Clinical trials identifier: NCT03832049).

The aim of ESCUDDO and these other trials is to continue to impact global policy recommendations by providing actionable evidence for the protection afforded by one dose of the HPV vaccines.

Study Design

There are two components to the study: (1) a controlled, randomized, double-blinded non-inferiority clinical trial to compare one-dose to two-dose vaccination; and (2) a concurrent epidemiologic survey for HPV infection status among unvaccinated women.

The trial enrolled >20,000 girls aged 12–16 years residing in Costa Rica. Participants were randomized in two stages to one of four arms (one dose of the bivalent vaccine, two doses of the bivalent vaccine, one dose of the nonavalent vaccine, or two doses of the nonavalent vaccine). The first randomization occurred at enrollment; participants were assigned to receive one of the two study vaccines. The second randomization occurred at the second visit; participants were assigned to receive one or two doses of the corresponding HPV vaccine. Girls randomized to the one-dose arm received an active control (i.e. Tdap) at the time of the second vaccine dose. After vaccination, girls are followed every six months for five years to assess the presence of persistent cervical HPV infections and antibody titers, by dose group and vaccine type. In the U.S., HPV vaccines  are licensed for two doses in younger recipients and three doses in older recipients. At each visit, participants complete a questionnaire and provide a urine sample. They may give blood samples. Participants 15 years and older use a swab to collect cells from their cervix and vagina.

The epidemiologic HPV survey enrolls a group of unvaccinated women from the same geographic areas; they range in age from 16 to 22 years. These women attend three study visits six months apart to determine their HPV DNA status. They are offered HPV vaccination.

ESCUDDO will generate data that public health policy makers need to make evidence-based decisions related to large scale implementation of sustainable, cost-effective HPV vaccine programs. Evidence of strong protection from a single-dose of either HPV vaccine may enable nations to introduce HPV vaccination or to achieve extensive population coverage by vaccinating a much larger number of HPV-naïve individuals, which, in combination with herd immunity, will result in decreased cervical cancer incidence and mortality over time. See the ESCUDDO trial (NCT03180034).

ESCUDDO is a Cancer Moonshot Initiative in the Intramural Research Program of the NIH, with additional support provided  by the NCI, the Bill & Melinda Gates Foundation, the National Institutes of Health Office of Research on Women’s Health, and the International Agency for Research on Cancer.
For more information, contact Dr. Aimée R. Kreimer.
Infections and Immunoepidemiology Branch - Research Areas