Vaccines that protect against human papillomavirus (HPV) infection can substantially reduce the risk of cervical cancer and other cancers attributable to HPV infection. However, HPV vaccination rates are too low, especially in countries with very high rates of cervical cancer. These vaccines are expensive, and giving multiple doses can be difficult, especially in low-resource settings. Researchers from DCEG and Costa Rica conducted the trial to determine if one dose of the HPV vaccines works as well as two doses in young women.
Public Health Impact
ESCUDDO was part of the Cancer Moonshot Initiative. The trial results were published in December 2025, showing non-inferiority of one dose, compared to two doses. Two doses 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.
In the U.S., HPV vaccines were licensed for two doses in younger recipients and three doses in older recipients. In January 2026, the Department of Health and Human Services announced plans for the CDC to revise its recommendation to just one dose of this vaccine, citing “recent scientific studies have shown that one dose of the HPV vaccine is as effective as two doses."
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 over a decade 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 were 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 were 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. At each visit, participants completed a questionnaire and provided a urine sample. They also gave a blood sample every 12 months. Participants 15 years and older used 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 ranged in age from 16 to 22 years. These women attended two study visits six months apart to determine their HPV DNA status. They were offered HPV vaccination.
See the ESCUDDO trial Clinicaltrials.gov (NCT03180034).
ESCUDDO was a Cancer Moonshot Initiative in the Intramural Research Program of the NIH, with additional support provided by the NCI and the 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
Study Results and Publications
ESCUDDO succeeded in showing that one dose of HPV vaccine works as well as two doses to prevent infections with the types of HPV that cause most cervical cancers. After five years of follow-up, we found that a single dose of either a bivalent or nonavalent HPV vaccine provided similar protection to that of two doses. The vaccine effectiveness against HPV16 or HPV18 was at least 97% in each of the four trial groups.
ESCUDDO was designed to generate data that public health policymakers need to make evidence-based decisions related to large-scale implementation of sustainable, cost-effective HPV vaccine programs. By providing evidence of strong protection from a single dose of either HPV vaccine, ESCUDDO adds further support to the current WHO recommendation, with enormous public health potential to facilitate global HPV vaccination and achieve cervical cancer elimination goals.
Publications
Kreimer A, Porras C, Liu D, et al. Noninferiority of One HPV Vaccine Dose to Two Doses. N Engl J Med. 2025.
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