Publication / Source: Infectious Diseases Hub
Authors: Martha Powell, Future Science Group
The race towards a vaccine for Zika virus began after its designation as a Public Health Emergency by the WHO in February 2016. The disease was confirmed to cause neurological complications, specifically in neonates seen when pregnant mothers have become infected, initiating a surge in research and development.
However, this in itself raises some issues around creating a vaccine; for example, safety must be paramount when a key target group is women of child-bearing age, some of whom may already be pregnant. Moreover, in related flaviviruses, such as dengue, it has been demonstrated that sequential infections can be more severe, and questions around the cross-reactivity between Zika and dengue have been posed.
But there are not only challenges – there is also great promise. Yellow fever, another related flavivirus, has a successful vaccine providing lifelong immunity, and the WHO’s pipeline tracker currently highlights approximately 45 projects working towards a Zika vaccine .
In this article, I provide an overview of the current candidates in human clinical trials and how these vaccines are being assessed.
A whole-inactivated vaccine candidate, which is being developed by a number of partners, including Sanofi Pasteur (PA, USA) and the National Institutes of Allergy and infectious Diseases (NIAID; MD, USA), is one of the five candidate vaccines currently in Phase I trials.
This candidate, termed the Zika Purified Inactivated Virus (ZPIV) vaccine, consists of the whole virus that has been inactivated. There are currently four separate studies of the ZPIV vaccine underway [2–5], which are assessing factors such as safety, tolerability and optimal regimens. Although whole-inactivated approaches have many advantages, such as easy storage and no risk of causing disease, they are often reported to induce weaker immune responses compared with some other approaches. Therefore several doses, or boosters, may be required for protective immunity.
One of the trials will evaluate an accelerated vaccination schedule; in non-human primates experiments were carried out with a prime and booster dose after 4 weeks . Here, the researchers will assess the safety and immunogenicity of a variety of schedules in healthy adults, monitoring any adverse events.
In the other three Phase I trials teams will assess the efficacy of the vaccine in flavivirus-naïve patients compared with ‘primed’ individuals, who have been vaccinated against yellow fever and Japanese encephalitis . In addition they will evaluate the safety and reactogenicity of different doses in both naïve subjects and those from flavivirus-endemic areas, who may have been exposed to related viruses, such as dengue [3, 4]. The first results are expected to be completed by late 2018.
Another approach is using viral vector platforms, which can be replicating or non-replicating. In an ongoing Phase I trial, a live-attenuated recombinant Zika vaccine – termed MV-ZIKA-101 – is being assessed . The candidate, which is being developed by Themis Bioscience GmbH (Vienna, Austria), utilizes a well-established measles vaccine vector initially developed by researchers based at the Institut Pasteur (Paris, France). Selected Zika antigens – the membrane protein (PrM) and envelope protein (E) – have subsequently been inserted.
Themis comment that, as the vector forms the basis of all current vaccine candidates pioneered by the company, this would allow rapid upscaling if the candidate were to be successful. In addition, this approach is reported to provide durable immunity .
The clinical study will aim to identify the most suitable doses of the vaccine with regard to immunogenicity, safety and tolerability. Up to 48 healthy volunteers are hoped to enrol in the study, participating in three different vaccine regimens that will be compared with a placebo. Treatment groups will receive either one high-dose vaccine, or two administrations of either a high- or low-dose vaccine. Side effects will be assessed, as will the Zika-specific immune response elucidated by the vaccine. It is hoped the trial will produce initial results within 6 months of the first volunteers enrolling in April 2017.
Nucleic acid vaccines are a relatively new approach and include both DNA- and RNA-based approaches. At present, there are no licensed DNA vaccines for use in humans; however, the concept of vaccines employing host machinery to produce the relevant antigen molecules is promising. There are currently two DNA-based vaccine candidates in human clinical trials for Zika virus.
The first, GLS-5700 is being pioneered by GeneOne Life Science (Seoul, South Korea) and Inovio Pharmaceuticals (PA, USA), and contains a single plasmid encoding the prME antigen [8,9]. The candidate is currently in Phase I trials, in which the synthetic DNA plasmid vaccine is being delivered through electroporation.
There are two studies currently underway; the first is assessing safety and immunogenicity in 90 healthy participants from a non-endemic Zika region. The second is also looking at these indicators, but in dengue virus-seropositive participants. In preclinical testing, the synthetic vaccine was reported to produce robust antibody and T cell responses.
The second candidate, termed VRC-ZKADNA090-00-VP (Zika virus wildtype DNA vaccine), is being developed by NIAID. The DNA vaccine is based on antigens PrM and E, and is the only prospective Zika vaccine currently in Phase II trials [10–12].
NIAID is leading these trials and aims to enrol over 2000 participants. The trial consists of two branches; first, gaining more data on safety and the immune response induced by the vaccine. This will involve 90 participants and aims to determine an optimal vaccine dose . The second branch will hope to recruit 2400 volunteers in areas where there is active or potential mosquito transmission of Zika . These participants will be randomized to receive either a placebo or the vaccine in order to determine whether the vaccine protects against disease caused by natural Zika infection. All volunteers will be monitored for approximately 2 years , meaning the study is currently expected to be completed by 2019.
In order to obtain the required data, NIAID have stated that the trial may need to be expanded if Zika transmission decreases. In addition, DNA vaccines may not be without risk; for example, the vaccine must travel to the nucleus and become chromosomally integrated, which raises the question of adverse effects. However, previous data in mice and non-human primates have been promising.
RNA vaccines, another branch of nucleic acid vaccines, eliminate one issue raised by DNA vaccines – they only have to travel across one membrane of the host cell. In addition, there is no need for a promoter and the vaccine will also be active in non-dividing cells, unlike DNA vaccines.
An RNA vaccine, mRNA-1325, is currently being developed by Modern Therapuetics (MA, USA), and is in Phase I trials . mRNA-1325, which encodes the antigen prME, is being tested in healthy adult subjects and the study will assess safety, tolerability and immunogenicity. The organizers are hoping for approximately 90 participants, who will receive an injection of the vaccine or a placebo, and any adverse side effects will be monitored.
Does the solution need to be Zika-specific?
NIAID, in collaboration with pharmaceutical company SEEK (London, UK), are also in the midst of a Phase I trial of a broader vaccine against mosquito-borne diseases . The candidate, AGS-v, contains four synthetic proteins from mosquito salivary glands and takes a novel approach, producing an immune response to mosquito saliva, as opposed to a specific pathogen. This study will assess the experimental safety of the vaccine and its ability to stimulate an immune response. Sixty healthy individuals will be assigned to one of three vaccine regimens: receiving two vaccine doses; receiving two vaccine doses; both with an adjuvant; or receiving two placebo injections of sterile water .
Participants will then be exposed to Aedes aegypti mosquitoes (that are not carrying disease) and vaccinated participants will be assessed for a modified response to mosquito bites. The study is expected to last 10 months, being completed in mid-2018.
So, is a Zika vaccine imminent? Early results have been promising, and with many candidates in Phase I trials the pipeline has moved swiftly with good progress to date. However, there is still a long way to go and with no assurance of positive results moving forwards, there is no certainty of success.
- World Health Organization, WHO vaccine pipeline tracker https://docs.google.com/spreadsheets/d/19otvINcayJURCMg76xWO4KvuyedYbMZDcXqbyJGdcZM/pubhtml# (Accessed 19th May 2017)
- National Institute of Allergy and Infectious Diseases. Phase I, randomized, double-blinded, placebo-controlled dose de-escalation study to evaluate safety and immunogenicity of alum adjuvanted Zika Virus Purified Inactivated Vaccine (ZPIV) in adults in a flavivirus endemic area. https://clinicaltrials.gov/ct2/show/NCT03008122 NLM identifier: NCT03008122
- National Institute of Allergy and Infectious Diseases, Walter Reed Army Institute of Research. Zika Virus Purified Inactivated Vaccine (ZPIV) accelerated vaccination schedule study (Z001). https://clinicaltrials.gov/ct2/show/NCT02937233 NLM identifier: NCT02937233
- National Institute of Allergy and Infectious Diseases. ZIKA vaccine in naive subjects. https://clinicaltrials.gov/ct2/show/NCT02952833 NLM identifier: NCT02952833
- National Institute of Allergy and Infectious Diseases. A Phase 1, first-in-human, double-blinded, randomized, placebo-controlled trial of a Zika Virus Purified Inactivated Vaccine (ZPIV) with alum adjuvant in healthy Flavivirus-naive and Flavivirus-primed subjects. https://clinicaltrials.gov/ct2/show/NCT02963909 NLM identifier: NCT02963909
- Themis Bioscience GmbH. Zika-vaccine dose finding study regarding safety, immunogenicity and tolerability. https://clinicaltrials.gov/ct2/show/NCT02996890 NLM identifier: NCT02996890
- Life Science Austria. Themis: Zika vaccine – worldwide first live alternated vaccine http://lisavienna.at/en/news/themis-zika-vaccine-worldwide-first-live-alternated-vaccine (Accessed 19th May 2017)
- GeneOne Life Science, Inc. Study of GLS-5700 in healthy volunteers. https://clinicaltrials.gov/ct2/show/NCT02809443 NLM identifier: NCT02809443
- GeneOne Life Science, Inc. Study of GLS-5700 in dengue virus seropositive adults. https://clinicaltrials.gov/ct2/show/NCT02887482 NLM identifier: NCT02887482
- National Institute of Allergy and Infectious Diseases. Safety and immunogenicity of a Zika virus DNA vaccine, VRC-ZKADNA085-00-VP, in healthy adults. https://clinicaltrials.gov/ct2/show/NCT02840487 NLM identifier: NCT02840487
- National Institute of Allergy and Infectious Diseases. VRC 320: A Phase I, randomized clinical trial to evaluate the safety and immunogenicity of a Zika virus DNA vaccine, VRC-ZKADNA090-00-VP, administered via needle and syringe or needle-free injector, PharmaJet, in healthy adults. https://clinicaltrials.gov/ct2/show/NCT02996461 NLM identifier: NCT02996461
- National Institute of Allergy and Infectious Diseases. A Zika virus DNA vaccine in healthy adults and adolescents (DNA). https://clinicaltrials.gov/ct2/show/NCT03110770 NLM identifier: NCT03110770
- NIH News. Phase 2 Zika vaccine trial begins in U.S., Central and South America. nih.gov/news-events/news-releases/phase-2-zika-vaccine-trial-begins-us-central-south-america (Accessed 19th May 2017)
- Moderna Therapeutics, Biomedical Advanced Research and Development Authority. Safety, tolerability, and immunogenicity of mRNA-1325 in healthy adult subjects https://clinicaltrials.gov/ct2/show/NCT03014089 NLM identifier: NCT03014089
- National Institute of Allergy and Infectious Diseases. Study in healthy volunteers to evaluate the safety and immunogenicity of AGS-v, a universal mosquito-borne disease vaccine. https://clinicaltrials.gov/ct2/show/NCT03055000 NLM identifier: NCT03055000
- Infectious Diseases Hub. Could a new vaccine help protect against a broad range of mosquito-borne diseases? www.id-hub.com/2017/02/22/new-vaccine-help-protect-broad-range-mosquito-borne-diseases/ (Accessed 19th May 2017)
About the Author
Martha joined Future Science Group in November 2016 as Editor of Infectious Diseases Hub, and helped work towards its successful launch in March 2017. Martha has a BSc (Hons) in Biomedical Science from Durham University and possesses a keen interest in publishing and science communication.