Evidence map›Paper›PMID 37390836›Full record

Trial reportThe Lancet. Infectious diseases2023

Safety and immunogenicity of a purified inactivated Zika virus vaccine candidate in adults primed with a Japanese encephalitis virus or yellow fever virus vaccine in the USA: a phase 1, randomised, double-blind, placebo-controlled clinical trial.

Michael A Koren, Leyi Lin, Kenneth H Eckels, Rafael De La Barrera, Vincent Dussupt, Gina Donofrio, Erica L Sondergaard, Kristin T Mills, Merlin L Robb, Christine Lee and 19 more

Registry-linked trialOpen access · greenAbstract readRandomized Controlled TrialClinical Trial, Phase I
PubMed Full text at PMC Publisher
In one paragraph

Trial report in The Lancet. Infectious diseases, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02963909 (A Phase 1, First-in-Human, Double-blinded, Randomized, Placebo-controlled Trial to Evaluate the Safety, Reactogenicity, and Immunogenicity of an Alum Adjuvanted Zika Virus Purified Inactivated Vaccine), which is not on this map. Cited by 13 papers.

0numbers the graph read from it
0cells of the map it votes in
13citing papers in PubMed
6.1field-weighted citation impact, top 3% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT02963909 phase1completednot on this map

A Phase 1, First-in-Human, Double-blinded, Randomized, Placebo-controlled Trial to Evaluate the Safety, Reactogenicity, and Immunogenicity of an Alum Adjuvanted Zika Virus Purified Inactivated Vaccine (ZPIV) in Healthy Flavivirus-Naïve and Flavivirus-Primed Subjects

TypeinterventionalSponsorNational Institute of Allergy and Infectious Diseases (NIAID)Ran2016 to 2018Enrolled75ConditionsZika Virus InfectionArmsIXIARO, Placebo, YF Vax 17D Strain, Zika Virus Purified Inactivated Vaccine (ZPIV)
3 · Its place in the literature

Who cites it

13 citing papers in PubMed, 21 citations in OpenAlex.

  1. Article
  2. Article
  3. Article
  4. Review
  5. Human T Cell Responses to Flavivirus Vaccines.European journal of immunology · 2025
    Review
  6. Article
  7. Review
  8. Zika virus: an overview update.Current opinion in HIV and AIDS · 2025
    Review
  9. Review
  10. Article
  11. Review
  12. Article
  13. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

29 authors at 3 institutions in 1 country.

Michael A KorenViral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA. Electronic address: michael.a.koren.mil@health.mil.
Leyi LinViral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Kenneth H EckelsPilot Bioproduction Facility, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Rafael De La BarreraPilot Bioproduction Facility, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Vincent DussuptEmerging Infectious Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA; US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA; Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
Gina DonofrioEmerging Infectious Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA; US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA; Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
Erica L SondergaardClinical Trials Center, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Kristin T MillsClinical Trials Center, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Merlin L RobbHenry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
Christine LeeClinical Trials Center, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Oluwaseun AdedejiEmmes Corporation, Rockville, MD, USA.
Paul B KeiserViral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Justin M CurleyClinical Trials Center, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Nathanial K CopelandClinical Trials Center, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Trevor A CrowellEmerging Infectious Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA; US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA; Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
Jack N HutterClinical Trials Center, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Melinda J HamerClinical Trials Center, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Anais Valencia-RuizDiagnostic Countermeasures Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA; Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
Janice DardenDiagnostic Countermeasures Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA; Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
Sheila PeelDiagnostic Countermeasures Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA; Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
Mihret F AmareEmerging Infectious Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA; Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
Tsedal MebrahtuEmerging Infectious Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA; US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA; Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
Margaret CostanzoUS Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA; Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
Shelly J KrebsEmerging Infectious Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA; US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA; Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
Gregory D GromowskiViral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Richard G JarmanViral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Stephen J ThomasViral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Nelson L MichaelCenter for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Kayvon ModjarradEmerging Infectious Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Walter Reed Army Institute of Research · USHenry M. Jackson Foundation · USEmmes (United States) · US

Funding

Evaluation of Antibody Responses Elicited by Zika Vaccination in Flavivirus-naïve and -experienced IndividualsR01AI155983 · NIAID · HENRY M. JACKSON FDN FOR THE ADV MIL/MED · PI Vincent Dussupt · 2021 to 2026
$4.2M
NIAID NIH HHS R01 AI155983
6 · The paper itself

Abstract

backgroundZika virus infection is a threat to at-risk populations, causing major birth defects and serious neurological complications. Development of a safe and efficacious Zika virus vaccine is, therefore, a global health priority. Assessment of heterologous flavivirus vaccination is important given co-circulation of Japanese encephalitis virus and yellow fever virus with Zika virus. We investigated the effect of priming flavivirus naive participants with a licensed flavivirus vaccine on the safety and immunogenicity of a purified inactivated Zika vaccine (ZPIV).

methodsThis phase 1, placebo-controlled, double-blind trial was done at the Walter Reed Army Institute of Research Clinical Trials Center in Silver Spring, MD, USA. Eligible participants were healthy adults aged 18-49 years, with no detectable evidence of previous flavivirus exposure (by infection or vaccination), as measured by a microneutralisation assay. Individuals with serological evidence of HIV, hepatitis B, or hepatitis C infection were excluded, as were pregnant or breastfeeding women. Participants were recruited sequentially into one of three groups (1:1:1) to receive no primer, two doses of intramuscular Japanese encephalitis virus vaccine (IXIARO), or a single dose of subcutaneous yellow fever virus vaccine (YF-VAX). Within each group, participants were randomly assigned (4:1) to receive intramuscular ZPIV or placebo. Priming vaccinations were given 72-96 days before ZPIV. ZPIV was administered either two or three times, at days 0, 28, and 196-234. The primary outcome was occurrence of solicited systemic and local adverse events along with serious adverse events and adverse events of special interest. These data were analysed in all participants receiving at least one dose of ZPIV or placebo. Secondary outcomes included measurement of neutralizing antibody responses following ZPIV vaccination in all volunteers with available post-vaccination data. This trial is registered at ClinicalTrials.gov, NCT02963909.

findingsBetween Nov 7, 2016, and Oct 30, 2018, 134 participants were assessed for eligibility. 21 did not meet inclusion criteria, 29 met exclusion criteria, and ten declined to participate. 75 participants were recruited and randomly assigned. 35 (47%) of 75 participants were male and 40 (53%) were female. 25 (33%) of 75 participants identified as Black or African American and 42 (56%) identified as White. These proportions and other baseline characteristics were similar between groups. There were no statistically significant differences in age, gender, race, or BMI between those who did and did not opt into the third dose. All participants received the planned priming IXIARO and YF-VAX vaccinations, but one participant who received YF-VAX dropped out before receipt of the first dose of ZPIV. 50 participants received a third dose of ZPIV or placebo, including 14 flavivirus-naive people, 17 people primed with Japanese encephalitis virus vaccine, and 19 participants primed with yellow fever vaccine. Vaccinations were well tolerated across groups. Pain at the injection site was the only adverse event reported more frequently in participants who received ZPIV than in those who received placebo (39 [65%] of 60 participants, 95% CI 51·6-76·9 who received ZPIV vs three [21·4%] of 14 who received placebo; 4·7-50·8; p=0·006). No patients had an adverse event of special interest or serious adverse event related to study treatment. At day 57, the flavivirus-naive volunteers had an 88% (63·6-98·5, 15 of 17) seroconversion rate (neutralising antibody titre ≥1:10) and geometric mean neutralising antibody titre (GMT) against Zika virus of 100·8 (39·7-255·7). In the Japanese encephalitis vaccine-primed group, the day 57 seroconversion rate was 31·6% (95% CI 12·6-56·6, six of 19) and GMT was 11·8 (6·1-22·8). Participants primed with YF-VAX had a seroconversion rate of 25% (95% CI 8·7-49·1, five of 20) and GMT of 6·6 (5·2-8·4). Humoral immune responses rose substantially following a third dose of ZPIV, with seroconversion rates of 100% (69·2-100; ten of ten), 92·9% (66·1-99·8; 13 of 14), and 60% (32·2-83·7, nine of 15) and GMTs of 511·5 (177·6-1473·6), 174·2 (51·6-587·6), and 79 (19·0-326·8) in the flavivirus naive, Japanese encephalitis vaccine-primed, and yellow fever vaccine-primed groups, respectively.

interpretationWe found ZPIV to be well tolerated in flavivirus naive and primed adults but that immunogenicity varied significantly according to antecedent flavivirus vaccination status. Immune bias towards the flavivirus antigen of initial exposure and the timing of vaccination may have impacted responses. A third ZPIV dose overcame much, but not all, of the discrepancy in immunogenicity. The results of this phase 1 clinical trial have implications for further evaluation of ZPIV's immunisation schedule and use of concomitant vaccinations.

fundingDepartment of Defense, Defense Health Agency; National Institute of Allergy and Infectious Diseases; and Division of Microbiology and Infectious Disease.

Indexed as

Encephalitis Virus, JapaneseJapanese Encephalitis VaccinesViral VaccinesYellow Fever VaccineZika VirusZika Virus InfectionAdultAntibodies, NeutralizingAntibodies, ViralDouble-Blind MethodFemaleHumansImmunogenicity, VaccineMaleVaccines, InactivatedYellow FeverAntibodies, NeutralizingAntibodies, ViralJapanese Encephalitis VaccinesVaccines, InactivatedViral VaccinesYellow Fever Vaccine

Identifiers

PMID37390836
PMCPMC10877583
OpenAlexW4382199971

What OpenQuestion holds

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Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.