Where are We with the New Zika Vaccine?

Tanya Huang, Mercer University College of Pharmacy

The Zika virus (ZIKV) was first discovered in 1947 in Uganda, and infection cases were observed sporadically in Africa and Southeast Asia. The virus is primarily transmitted to humans through Aedes mosquitoes, which are also present in the United States (Aedes albopictus). Transmission through mosquito bites are implicated for pathogenic outbreaks. Other modes of transmission include sexual transmission and transfusion-related transmission. Although the virus is detectable in breast milk, transmission via breastfeeding has not yet been reported.    Zika virus infection are often asymptomatic (~80%) or exhibit mild symptoms that resolve in a few days. Common symptoms of the infection are fever, itchy maculopapular rash, nonpurulent conjunctivitis, arthralgia of small joints of the hands and feet, myalgia, and headache involving retro-orbital pain. Serious complications such as death, hemorrhagic complications, and/or hospitalizations due to infection are rare compared to other types of infections (e.g. yellow fever and dengue infections). [1]

The first large outbreak was in 2007 in Yap State in the Federated States of Micronesia, and it was estimated that about 73% Yap residents older than three years of age were infected with Zika virus. According to the World Health Organization (WHO), no deaths, hospitalization, or neurological complications were reported during this incidence. [2]  However, during another outbreak in French Polynesia in 2013, multiple cases of congenital malformation and increased cases of Guillain Barre Syndrome (GBS) were noted. [1,2] However, during the same outbreak, there was a concurrent dangue outbreak in the same region; therefore, it was unclear whether the increased incidences of GBS was solely due to Zika virus. In 2015, another outbreak was identified from Brazil and following this outbreak, the virus was detected in several other South and Central American countries and Caribbean regions. As a result, in early 2016, the WHO declared international public health emergency due to its association with congenital malformation in infants such as microcephaly and neurological complication. [2]  

Despite the outbreaks and their potential complications, there are no approved ZIKV vaccines or treatments available. However, a phase 1, open-label clinical trials is currently ongoing to evaluate the safety and immunogenicity of a new ZIKV vaccine. Recently, the preliminary report of the study published, and the results are summarized below. [3]

 

Safety and Immunogenicity of an Anti-Zika Virus DNA Vaccine — Preliminary Report: ZIKA-001
Design Non-randomized, multicenter, open-label, parallel assignment study; N= 40
Objective To determine the safety, tolerability, and immunogenicity of GLS-5700, a Zika virus (ZIKV) DNA vaccine, by intradermal injection followed by electroporation in Dengue Virus
Study Groups GLS-5700 1 mg (n= 20)

GLS-5700 2 mg (n= 20)

Methods Healthy patients ages 18-65 who tested negative for dengue virus infection were assigned to receive either GLS-570 1 mg or 2 mg dose in a 0.1 mL intradermal injection followed by electroporation at the site of injection to increase vaccine immunogenicity. Patients received either one or two vaccine injections in their deltoid region at baseline, four weeks, and 12 weeks. The electroporation was completed using CELLECTRA-3P with four 52-msec pulses at 0.1 each session. Escalation of the doses from 1 mg to 2 mg and the remaining 1 mg study group were completed after review of the first dose of vaccine in the first five participants in the 1 mg vaccine group by data and safety monitoring committee.
Duration July 2016- December 2017(estimated)
Primary Outcome Measure Mean change from baseline in safety laboratory measures; incidence of solicited adverse events after vaccination; incidence of unsolicited adverse events after vaccination; incidence of serious adverse events.

  • Time Frame: Day 0 through Week 60 for all measures
Baseline Characteristics
GLS-5700 1 mg (n= 20) GLS-5700 2 mg (n= 20) Overall (N= 40)
Gender
Male 9 7 16
Female 11 13 24
Race
American Indian or Alaska Native 0 0 0
Asian 0 0 0
Black or African American 7 2 9
Native Hawaiian, Pacific Islander 0 0 0
White 13 18 31
Other 0 0 0
Ethnicity
Hispanic or Latino 4 8 12
Not Hispanic or Latino 16 12 28
Age (years)
Median 37 44 38
Q1, Q3 29.5, 50.0 30.5, 55.0 30.0, 54.0
Min, Max 22, 65 19, 62 19, 65
Results
Treatment-emergent adverse events by system organ class (any grade)
Preferred term GLS-5700 1 mg (n=20) n(%) 1 GLS-5700 2 mg (n= 20) n(%) Overall (N= 40) n (%) Related events (n)
Subjects with at Least One TEAE 15 (75.0) 18 (90.0) 33 (82.5)
Blood & lymphatic system disorders 2 (10.0) 0 2 (5.0)
Anemia 1 (5.0) 0 1 (2.5) 0
Neutrophilia 1 (5.0) 0 1 (2.5) 0
Neutrophil count decreased 2 0 1 (5.0) 1 (2.5) 0
Gastrointestinal disorders 2 (10.0) 3 (15.0) 5 (12.5)
Abdominal pain 1 (5.0) 0 1 (2.5) 0
Abdominal tenderness 0 1 (5.0) 1 (2.5) 0
Diarrhea 1 (5.0) 0 1 (2.5) 0
Nausea 0 2 (10.0) 2 (5.0) 2
Administration site conditions
Application site reaction 2 (10.0) 1 (5.0) 3 (7.5) 3
Application site scab 4 (20.0) 3 (15.0) 7 (17.5) 7
Injection site erythema 9 (45.0) 10 (50.0) 19 (47.5) 19
Injection site pain 2 (10.0) 7 (35.0) 9 (22.5) 9
Injection site pruritus 6 (30.0) 9 (45.0) 15 (37.5) 15
Injection site swelling 2 (10.0) 4 (20.0) 6 (15.0) 6
General Disorders
Fatigue 1 (5.0) 0 1 (2.5) 1
Malaise 1 (5.0) 2 (10.0) 3 (7.5) 3
Oedema peripheral 3 1 (5.0) 0 1 (2.5) 0
Infections 3 (15.0) 10 (50.0) 13 (32.5) 1
Application site infection 4 0 1 (5.0) 1 (2.5) 1
Blastocystis infection 0 1 (5.0) 1 (2.5) 0
Bronchitis 0 1 (5.0) 1 (2.5) 0
Influenza 0 1 (5.0) 1 (2.5) 0
Nasopharyngitis 2 (10.0) 5 (25.0) 7 (17.5) 0
Pharyngitis streptococcal 0 1 (5.0) 1 (2.5) 0
Sinusitis 1 (5.0) 0 1 (2.5) 0
Upper respiratory tract infection 0 3 (15.0) 3 (7.5) 0
Urinary tract infection 1 (5.0) 1 (5.0) 2 (5.0) 0
Vulvovaginal mycotic infection 1 (5.0) 0 1 (2.5) 0
Injury 1 (5.0) 1 (5.0) 2(5.0)
Fall 0 1 (5.0) 1 (2.5) 0
Laceration 1 (5.0) 0 1 (2.5) 0
Investigations 0 2 (10.0) 2 (5.0)
Endoscopy gastrointestinal 0 1 (5.0) 1 (2.5) 0
Metabolism and nutrition disorder 2 (10.0) 0 2 (5.0)
Hyperkalaemia 1 (5.0) 0 1 (2.5) 0
Hypoglycaemia 1 (5.0) 0 1 (2.5) 0
Musculoskeletal disorders 3 (15.0) 4 (20.0) 7 (17.5)
Arthralgia 2 (10.0) 1 (5.0) 3 (7.5) 3
Monarthritis 0 1 (5.0) 1 (2.5) 0
Musculoskeletal pain 1 (5.0) 1 (5.0) 2 (5.0) 1
Myalgia 2 (10.0) 2 (10.0) 4 (10.0) 4
Nervous system disorder 3 (15.0) 6 (30.0) 9 (22.5)
Dizziness 0 1 (5.0) 1 (2.5) 1
Headache 3 (15.0) 3 (15.0) 6 (15.0) 6
Hypoaesthesia 5 0 1 (5.0) 1 (2.5) 1
Migraine 0 1 (5.0) 1 (2.5) 1
Sinus headache 0 1 (5.0) 1 (2.5) 0
Psychiatric disorder 1 (5.0) 1 (5.0) 2 (5.0)
Attention Deficit/Hyperactivity 1 (5.0) 0 1 (2.5) 0
disorder
Nightmare 0 1 (5.0) 1 (2.5) 1
Reproductive system and breast 1 (5.0) 0 1 (2.5)
Disorders
Breast cyst 1 (5.0) 0 1 (2.5) 0
Skin and Subcutaneous tissue disorder 2 (10.0) 1 (5.0) 3 (7.5)
Eczema 1 (5.0) 0 1 (2.5) 0
Erythema 1 (5.0) 1 (5.0) 2 (5.0) 2
Hyperhidrosis 0 1 (5.0) 1 (2.5) 1
Vascular disorder 1 (5.0) 0 1 (2.5)
Hypotension 1 (5.0) 0 1 (2.5) 1

1: Percent related is determined as # of events divided by total events participants in the group
2: Grade 2 neutrophilia in subject with Grade 1 neutrophilia at baseline, determined by PI as not related
to study drug.
3: Edema in lower limbs, determined by PI as not related to study drug.
4: Transient purulence at injection site, resolved with local measures, considered as related to injection.
5: Hypoaesthesia constituted numbness in both arms starting a day after injection and lasting for 1 day, determined by PI as related to injection.

Geometric Mean Antibody Titers (95% CI) by week
1 mg dose 2 mg dose
Week Geometric mean 95% CI Geometric mean 95% CI
0 1 (1-1) 1 (1-1)
1 1.38 (0.8169-2.33) 1 (1-1)
4 3.085 (1.091-8.726) 14.23 (3.404-59.52)
6 21.28 (5.992-75.6) 125 (37.75-413.9)
12 15.43 (4.223-56.35) 38.18 (11.73-124.3)
14 1642 (347.3-7760) 2871 (705.3-11,688)
Antigen-specific IFN-୪ secreting cells was determined by IFN-୪ ELISpot assays
1 mg dose 2 mg dose
Week Median IQR Median IQR
0 7.085 (5-20.42) 0 (0-6.25)
4 6.67 (1.67-21.67) 12.5 (0-33.33)
6 12.5 (7.498-19.17) 58.33 (25-95)
14 35 (14.17-63.75) 28.33 (18.34-127.5)
Adverse Events Serious Adverse Events: N/A
Percentage that Discontinued due to Adverse Events: N/A
Study Author Conclusions The study shows initial safety and immunogenicity of a vaccine encoding the DNA of ZIKV premembrane and envelope antigens administered by electroporation.The GLS-5700 vaccine appears to have a protective response against ZIKV strains.  

 

Limitation of the data is that this is preliminary results. The study is expected to be completed by December 2017. Additionally, as a phase 1 trial, even the complete data may provide limited scope of evidence regarding its efficacy and safety, especially in a large population. Although the preliminary results may suggest the vaccine’s protective response, further trials of safety and efficacy of the vaccine will be warranted before being implemented as standard practice.

References

[1]Sampathkumar P, Sanchez JL. Zika virus in the Americas: A review for clinicians.Mayo Clin Proc. 2016;91(4):514-21.

[2] Kindhauser MK, Allen T, Frank V, Santhana R, Dye C. Zika: the origin and spread of a mosquito-borne virus. Bull World Health Org. 2016;94(9):675-686C.

[3] Tebas P, Roberts CC, Muthumani K, et al. Safety and immunogenicity of an anti-Zika virus DNA vaccine – Preliminary report. N Engl J Med. 2017. [Epub ahead of print]. doi: 10.1056/NEJMoa1708120.

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