Advancements in Zika virus vaccine development
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Zika virus is an important mosquito-borne pathogen with significant public health concerns. Zika vaccine development is an ongoing area of research with several candidates in the pipeline.
Epidemiology
An RNA virus belonging to the Flaviviridae family, Zika was discovered in 1947 in a Rhesus macaque monkey in the Zika forest in Uganda. The virus is primarily transmitted by the bite from an infected mosquito from the Aedes genus, mainly Aedes aegypti. Zika virus can also be transmitted by an infected individual to others through sexual contact, blood transfusions or laboratory exposure.
Diagnosing Zika infections can be difficult because many infections are asymptomatic. Those who develop symptoms can present with fever, rash, conjunctivitis, muscle and joint pain, malaise and headache.
Although most patients recover with supportive care, serious complications can occur. Guillain-Barré syndrome has been described in adults; however, this is a rare complication. The most devastating consequences of Zika infection occur during pregnancy. Zika infection during pregnancy can cause miscarriage, preterm birth and infants to be born with microcephaly or other congenital malformations.
Since its discovery, sporadic outbreaks have occurred, but because symptoms of Zika are like those of many other diseases, it is possible that cases go undiagnosed. A large outbreak of Zika infections occurred in Brazil beginning in 2015 and subsequently spread to other countries and territories. Because of its link to birth defects, WHO declared Zika virus a Public Health Emergency of International Concern for much of 2016. As of December 2022, 89 countries and territories have documented evidence of mosquito-transmitted Zika virus.
Vaccine development
Because there are no available treatments, prevention of Zika virus infection is incredibly important.
WHO and the United Nations International Children’s Emergency Fund have developed a Zika virus vaccine target product profile (TPP) that describes the minimal product characteristics for these vaccines. The primary objective of the TPP is to help protect against congenital Zika virus syndrome, especially during public health emergencies or outbreaks. There are now several vaccine candidates in development, most of which are in the early phase of development and clinical trials.
A phase 1 clinical trial evaluated dosing, safety and immunogenicity of a purified, inactivated, aluminum hydroxide-adjuvanted whole Zika virus vaccine (TAK-426) in adults aged 18 to 49 years in the United States and Puerto Rico. Two doses of placebo or vaccine were administered by intramuscular injection 28 days apart. Part 1 of the study was in participants who were flavivirus-naive. The three studied doses of the vaccine formulation were well tolerated, and all participants without prior flavivirus exposure developed a robust dose-dependent neutralizing antibody response. Part 2 of the study consisted of vaccinating participants with prior exposure to a flavivirus, which was determined through prevaccination screening to antibodies from 13 flaviviruses. These individuals also had a similar dose-dependent neutralizing antibody response, but a significant increase in geometric mean titers (GMTs) after the second dose was not seen. The GMTs were also lower than observed in the flavivirus-naive group.
The success of COVID-19 messenger RNA vaccines have propelled the research of this vaccine technology into other infections, including Zika. The results of two phase 1 placebo-controlled trials were recently reported for two Zika virus vaccine candidates, mRNA-1325 and mRNA-183. The first-generation mRNA-1325 vaccine is based on structural proteins from a Micronesia 2007 Zika virus isolate, whereas mRNA-183 is a second-generation mRNA vaccine based on an isolate from Brazil, which contains different amino acid residues. Researchers administered the vaccines as a two-dose series 28 days apart. There was a significant difference in virus neutralizing antibody (nAb) responses between the two vaccines. Although mRNA-1325 was well tolerated, unfortunately the nAb response was poor. In contrast, mRNA-1893 induced a robust nAb response that persisted for at least 12 months. No serious adverse events occurred, with the most common reported side effects being injection site pain, fatigue, headache and myalgia. Based on these data, mRNA-183 is continuing to be developed. A phase 2 trial (NCT04917861) of the vaccine candidate is currently ongoing in individuals living in endemic and nonendemic flavivirus areas.
A DNA vaccine platform has been used to develop vaccine candidates for pathogens such as West Nile virus, Ebola virus and others. DNA vaccines can be made rapidly and induce both humoral and cellular immunity, making them an attractive option for vaccine development. The safety and immunogenicity of an anti-Zika virus DNA vaccine (GLS-5700) was evaluated in an open-label clinical trial. Participants received either a 1 mg or 2 mg dose of GLS-5700 vaccine by intradermal injection, followed by electroporation at the site of the inoculation to increase the immunogenicity of the vaccine. Booster doses were given at weeks 4 and 12. Antibody levels assessed at week 14 showed 100% seroconversion for binding antibodies in both dose groups. The GMTs were higher for the 2 mg dose, indicating the antibody response is dose dependent. The vaccine was well tolerated with no severe adverse reactions.
Other platforms have also been studied for Zika virus vaccine production. These include viral vector vaccines, live-attenuated vaccines, peptide-based vaccines, recombinant protein vaccines and salivary protein vaccines.
Providing passive immunization by using monoclonal antibodies (mAbs) is also an area of interest. Not all mAbs have provided strong protection against Zika virus, which could still put patients at risk of developing serious consequences of Zika viral infection. However, a newer mAb has been developed that targets a Zika virus-specific nonstructural protein, which has shown promise by being protective without inducing adverse effects of disease in a mouse model.
Although the reported incidence of Zika virus infection has decreased since the outbreak in the Americas, we are still at risk for another epidemic. New data from Brazil also show that patients may be reinfected with Zika virus because of the developing genomic diversity of the virus.
Although there have been substantial breakthroughs in vaccine development for Zika virus infections, there will not be an approved vaccine for some time. In the meantime, many will unfortunately continue to be at risk for developing complications from this infection.
References:
- Castilho MC, et al. Emerg Infect Dis. 2024;doi:10.3201/eid3002.230122.
- Essink B, et al. Lancet Infect Dis. 2023;doi:10.1016/S1473-3099(22)00764-2.
- Han HH, et al. Lancet Infect Dis. 2021;doi:0.1016/S1473-3099(20)30733-7.
- Tebas P, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa1708120.
- Wang Y, et al. Vaccines. 2022;doi:10.3390/vaccines10111816.
- WHO. WHO/UNICEF Zika virus (ZIKV) vaccine target product profile (TPP). https://www.who.int/publications/m/item/who-unicef-zika-virus-(zikv)-vaccine-target-product-profile-(tpp). Published Feb. 8, 2017. Accessed Feb. 27, 2024.
- WHO. Zika virus. https://www.who.int/news-room/fact-sheets/detail/zika-virus. Published Dec. 8, 2022. Accessed Feb. 27, 2024.
- Yu L, et al. mBio. 2021;doi:10.1128/mbio.03179-20.
For more information:
Jeff Brock, PharmD, MBA, BCIDP, is a Healio | Infectious Disease News Editorial Board Member and infectious disease pharmacy specialist at Mercy Medical Center in Des Moines, Iowa. He can be reached at jeff.brock@mercyoneiowa.org.
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