Elsevier

The Lancet

Volume 391, Issue 10120, 10–16 February 2018, Pages 563-571
The Lancet

Articles
Preliminary aggregate safety and immunogenicity results from three trials of a purified inactivated Zika virus vaccine candidate: phase 1, randomised, double-blind, placebo-controlled clinical trials

https://doi.org/10.1016/S0140-6736(17)33106-9Get rights and content

Summary

Background

A safe, effective, and rapidly scalable vaccine against Zika virus infection is needed. We developed a purified formalin-inactivated Zika virus vaccine (ZPIV) candidate that showed protection in mice and non-human primates against viraemia after Zika virus challenge. Here we present the preliminary results in human beings.

Methods

We did three phase 1, placebo-controlled, double-blind trials of ZPIV with aluminium hydroxide adjuvant. In all three studies, healthy adults were randomly assigned by a computer-generated list to receive 5 μg ZPIV or saline placebo, in a ratio of 4:1 at Walter Reed Army Institute of Research, Silver Spring, MD, USA, or of 5:1 at Saint Louis University, Saint Louis, MO, USA, and Beth Israel Deaconess Medical Center, Boston, MA, USA. Vaccinations were given intramuscularly on days 1 and 29. The primary objective was safety and immunogenicity of the ZPIV candidate. We recorded adverse events and Zika virus envelope microneutralisation titres up to day 57. These trials are registered at ClinicalTrials.gov, numbers NCT02963909, NCT02952833, and NCT02937233.

Findings

We enrolled 68 participants between Nov 7, 2016, and Jan 25, 2017. One was excluded and 67 participants received two injections of Zika vaccine (n=55) or placebo (n=12). The vaccine caused only mild to moderate adverse events. The most frequent local effects were pain (n=40 [60%]) or tenderness (n=32 [47%]) at the injection site, and the most frequent systemic reactogenic events were fatigue (29 [43%]), headache (26 [39%]), and malaise (15 [22%]). By day 57, 52 (92%) of vaccine recipients had seroconverted (microneutralisation titre ≥1:10), with peak geometric mean titres seen at day 43 and exceeding protective thresholds seen in animal studies.

Interpretation

The ZPIV candidate was well tolerated and elicited robust neutralising antibody titres in healthy adults.

Funding

Departments of the Army and Defense and National Institute of Allergy and Infectious Diseases.

Introduction

The emergence of Zika virus as a major cause of microcephaly and other neurological defects1, 2, 3, 4, 5, 6 echoes the devastating congenital effects associated with other viral infections during pregnancy.7 The historical experience with the eradication of congenital rubella syndrome by aggressive vaccination campaigns suggests that similar results could be achieved for Zika virus.8 In addition, infection with Zika virus poses substantial risks to infected adults.9, 10, 11, 12 Unknown duration of infectivity, continued viral transmission, mosquito vector expansion, and vulnerability of immunologically naive populations underscore the continued need for a safe and effective vaccine,13, 14 particularly as Zika virus becomes endemic in locations worldwide and threatens to resurge to previous epidemic or unseen pandemic proportions.13, 14

Previous experience with other flaviviruses and inactivated virus vaccine platforms has facilitated the accelerated development of a purified, formalin-inactivated Zika virus vaccine (ZPIV) candidate. The ZPIV candidate derives from a 2015 Puerto Rican Zika virus strain (PRVABC59), which is closely related to the 2015 Brazilian strain, SPH2015, and is circulating through much of Latin America.15 Preclinical studies with ZPIV have shown complete protection from viraemia after wild-type challenge with Zika virus strain PRVABC59 or SPH2015 in immunocompetent mice16 and non-human primates.17 Vaccination in these species has induced robust antibody responses, with particularly high titres among non-human primates (50% microneutralisation titre [MN50] 3·66log) 2 weeks after completion of a two-dose course with 5 μg vaccine on days 1 and 29.16, 17 This dose and schedule was selected based on the experience of the Walter Reed Army Institute of Research, Silver Spring, MD, USA, with other inactivated flavivirus vaccines. Adoptive transfer of purified IgG from vaccinated mice and non-human primates into virus-naive animals of the same species provided complete protection from Zika virus challenge with MN50 between one (1:10) and two (1:100) logarithms,16, 17 which is similar to accepted correlates for other flaviviruses, such as Japanese encephalitis virus, tick-borne encephalitis virus, and yellow fever virus vaccines.18 These data provided a mechanistic correlate of protective immunity and a basis on which to advance testing to human trials.16, 17

Research in context

Evidence before this study

The Zika virus outbreak has had devastating effects on children and families across the western hemisphere since 2015. Although no longer declared a public health emergency of international concern, cases of Zika virus infection are still occurring, and the threat of a resurgent epidemic remains. Thus, a safe and effective vaccine is needed to prevent and control Zika virus spread and the consequent complications. The Walter Reed Army Institute of Research, Silver Spring, MD, USA, applied its long-standing expertise, infrastructure, and partnerships in developing and testing vaccines against other flaviviruses to enable rapid design, manufacture, and assessment of an inactivated and purified whole Zika virus vaccine with aluminium hydroxide gel adjuvant. Throughout the development and testing of this vaccine, we searched the biomedical literature for new information on Zika virus and associated countermeasures. We searched PubMed with the terms “Zika”, “flavivirus”, “congenital Zika syndrome”, “vaccine”, “Zika vaccine”, and “flavivirus vaccine” for articles published up to Oct 31, 2017, with no other parameters applied. We additionally reviewed electronic updates from the Centers for Disease Control and Prevention, WHO, and the Pan-American Health Organization on the dynamic epidemiology of the Zika epidemic, and tracked other clinical trials of Zika virus registered with ClinicalTrials.gov. Several Zika vaccine platforms have shown efficacy in preclinical animal studies. One study has reported on the safety and immunogenicity of a DNA vaccine. We found no reports of inactivated Zika virus vaccine being tested in human beings.

Added value of this study

Our purified formalin-inactivated Zika virus vaccine candidate showed a tolerable safety profile and yielded immunogenicity characterised by neutralising antibody titres that exceeded the protective threshold seen in non-human primate studies. Our findings will be useful to the continuing effort to develop a preventive vaccine against Zika virus. Additionally, passive antibody transfer from the serum of vaccine recipients into mice indicated a potential mechanistic correlate of protection.

Implications of all the available evidence

The whole inactivated virus platform on which our Zika vaccine candidate is based has resulted in several safe and effective vaccines, including some licensed for other flaviviruses, such as Japanese encephalitis and tick-borne encephalitis. Our results and previous findings suggest that the inactivated platform is a viable candidate for advanced development.

We report the early safety and immunogenicity results of three phase 1 trials of ZPIV. We also assessed adoptive transfer of purified antibody from vaccine recipients into mice to assess protection against viraemia.

Section snippets

Study design and population

The three single-centre studies included in this aggregate analysis are all phase 1, randomised, placebo-controlled, double-blind trials. Done at Walter Reed Army Institute of Research (WRAIR), Saint Louis University, Saint Louis, MO, USA (SLU), or Beth Israel Deaconess Medical Center, Boston, MA, USA (BIDMC), each was designed to address a unique question about background immunity, vaccine dose, or vaccination schedule. The WRAIR trial is assessing the effect of pre-existing flavivirus

Results

Between Nov 7, 2016, and Jan 25, 2017, we enrolled 68 participants in the three trials. One participant at SLU was inadvertently randomly assigned treatment and enrolled due to a screening failure, but the error was recognised before this individual received any vaccinations. Thus, 67 individuals were vaccinated (55 with ZPIV and 12 with placebo) on days 1 and 29 and were followed up to day 57 for this analysis (table 1, figure 1). The mean age of all study participants was 31·5 years (SD 8·9),

Discussion

Two intramuscular injections of 5 μg ZPIV with aluminium hydroxide adjuvant 4 weeks apart led to no clinically meaningful adverse events and elicited neutralising antibody responses in nearly all individuals at 2–4 weeks after the second dose. The primary immunogenicity endpoint of GMT at day 57 reached a threshold titre (1:100) that exceeded the thresholds for protection in previous mouse and non-human primate studies,16, 17 where adoptive transfer of vaccine-elicited antibodies at MN50 1:60

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