Current status of Zika virus vaccine development

Michael Nissen FRACP FRCPA

Director, Scientific Affairs & Public Health

GSK Vaccines Asia-Pacific, Singapore

Travel Vaccine Update-MVEC 31 July 2017

GSK Asia HQ- Singapore: Artistic impression

Disclosure

Employee of GlaxoSmithKline Vaccines& hold stock on LSTE

Adjunct Professor at Children’s Health Research Centre, University of QLD, Australia

Specific opinions expressed are in my academic & personal capacity as an invited

speaker for this meeting, and do not necessarily reflect the position of GSK

Zika Virus (ZIKV)

▪ RNA virus 1

▪ Flavivirus genus1

▪ 2 lineages: African & Asian 2,3

▪ Reservoirs: humans, non humanprimates 1

▪ ZIKV enzootic cycle probablymaintained primarily in monkey/mosquito cycle in Africabut a human-mosquito-humancycle obviously exists (Yap, French Polynesia, etc.) 1

▪ Antibodies detected in numerous animal species (bats, rodents, sheep, goats, ...) 1

1. Musso & Gubler. Clin Microbiol Rev 2016; 29: 487-524. 2. Enfissi et al. Lancet 2016; 387:227-8. 3. Haddow et al. PLoS Negl Trop Dis 2012; 6:e1477. 4. Duong &

Buchy. Int J Infect Dis (in revision)

Phylogenetic tree of flaviviruses 4

ZIKV: Zika virus; DENV: dengue virus; WNV: West Nile virus; JEV: Japanese encephalitis virus; YKV: Yellow fever virus

ZIKV

Asian

lineage

African

lineage

Mo

squ

ito

-bo

rne

fla

viv

iru

se

sT

ick-b

orn

e

flaviv

iruses

DENV

WNV

JEV

YFV

ZIKV Transmission

▪ Bite of an infected female mosquito of the Aedes species (Culex unlikely) 1,2

▪ Blood transfusions & laboratory-acquired infections 1,3

▪ Sexual intercourse (semen up to 80 days, vaginal secretions ~2 weeks) 3,4

▪ Maternal-fetal transmission: during all trimesters of pregnancy and during the perinatal period 3,5

▪ Breast milk found positive for ZIKV: risk of transmission? 1

1 Barzon et al. FEMS Microbiol Lett 2016; 363(18).pii: fnw202 2. Huang YS et al. Vector Born Zoonotic Dis 2016. DOI: 10.1089/vbz.2016.2058 3. Abushouk AI et al. J Clin Virol 2016; 84:53-58. 4. Prisant N et al. Clin Infect Dis 2016; pii: ciw699. 5. Besnard M et al. Euro Surveill 2014; 19(13). pii: 20751

Copyright free picture obtained from:

https://commons.wikimedia.org/wiki/File:Aedes_aegypti_during_bloo

d_meal.jpg

ZIKV Clinical diagnosis

▪ Incubation period: ~3-12 days 1

▪ Usually very mild disease; ~ 3/4 infections are unnoticed 2

▪ Fever <38.5°C 3

▪ Fatigue 3

▪ Maculopapular rash 3

▪ Myalgias, arthralgias, joint swelling (hands & feet ++), headache, malaise 2,3

▪ Nonpurulent conjunctivitis, conjunctival hyperemia 2

▪ Spectrum of disease overlapsthat caused by DENV and CHIKV 1,3

1. Ioos S et al. Med Mal Infect 2014; 44:302-7. 2 Musso & Gubler. Clin Microbiol Rev 2016; 29:487-524. 3. Kelser EA. Microbes Ingect 2015; 18: 163-6.

Copyright free image from: http://phil.cdc.gov/phil/details.asp

ZIKV Neurological complications

▪ Guillain-Barré syndrome (GBS):

– 18 countries with increased incidence of GBS and/or confirmation of ZIKV infection among GBS cases 1

– French Polynesia: 20 fold increasedincidence during Zika outbreak 2

▪ Microcephaly:

– >20 countries reported microcephalyand other CNS malformations potentially associated with Zikainfections 1

– Close to 2000 cases reported (1st Sept 2016) 1

– Mainly decreased cortical developmentand atrophy 3

– ZIKV Ag or RNA found in brain and placenta of fetus with microcephaly 4

1. . WHO. Zika virus, Microcephaly and Guillain-Barré syndrome. 2016. Available at: http://www.who.int/emergencies/zika-virus/situation-report/1-september-2016/en/

(accessed September 1 2016). 2. Oehler E et al, Euro Surveill 2014; 19(9). pii: 20720 3. de Oliveira Melo et al. JAMA Neurol 2016;

doi:10.1001/jamaneurol.2016.3720 4. Barzon et al. FEMS Microbiol Lett 2016; 363(18).pii: fnw202

Normal head size

Microcephaly

Copyright free images from

http://www.wikidoc.org/index.php/File:Microcephaly_2.jpg

71. Lipsitch & Cowling. Science 2016; 353: 1094-5. 2. Marston et al. N Engl J Med 2016; 375:1209-12.

Where?

→ Multiple sites

Placebo group?

• Epidemics may

wane & recur 1

•Flavivirus-naïve

& non-naïve

populations 1

Who is at priority?

• Women of

childbearing age

with no previous

ZIKV infection &

not pregnant 1

• Risk for fetus

during incident

pregnancies? 1

•sexual partners? 2

• Controversial

during Ebola

vaccine trials 1

• Probably

acceptable for

Zika in healthy

adults (usually

non-severe) 1

Zika vaccination

8

9

10

End point =

symptomatic

infection 1

1

2

End point =

symptomatic &

asymptomatic

infections 1

Active surveillance with regular

samples collection 1

Vaccine development strategies (1)

“Traditional” approach: phase 1 & 2 assess safety and

immunogenicity

(including in flavivirus-naïve and non-naïve groups) 1

1. Marston et al. N Engl J Med 2016; 375:1209-12.

Human challenge for

efficacy and additional

human safety studies 1

Animal challenge for

efficacy, additional

human safety studies 1

111. Available at: http://fortune.com/2016/10/04/drugmakers-zika-vaccine/ 2. Dawes BE et al. npj Vaccines 2016; 1: 16007; doi: 10.1038/npjvaccines.2016.7

1

1

> 60 research institutes and companies are

working on the development of Zika

vaccines 2

12

13

Recombinant

subunit

Examples of Zika vaccine development strategies

Recombinant

chimeric liveYF 17D, DENV, JEV, measles,..

Single-

round

replicating

viruses

DNA &

RNA

Purified

inactivated

virus

VLP

virus-vectored

vaccines

Virus-

vectored

Adenovirus oral

Dawes BE et al. npj Vaccines 2016; 1: 16007; doi: 10.1038/npjvaccines.2016.7

Live-attenuated virus vs. inactivated-virus vaccines?

141. Marston et al. N Engl J Med 2016; 375:1209-12.

are periods of immune system

change and, consequently,

increased vulnerability to

infection1

Live-

attenuated

PROS: May be protective after

a single dose 1

PROS: Better adapted for

pregnant women 1

CONS: Not adapted for

pregnant women 1

CONS: May need several doses

with delay for protective

immunity beyond peak of

vulnerability of fetus 1

Inactivated,

subunit,...

Gene-based vaccines are feasible

Direct gene transfer into mouse muscle in vivoWolff JA et al. 1990 Science : Vol. 247 pp. 1465-1468

Gene vaccination with naked plasmid DNA:

mechanism of CTL primingCorr M et al. J Exp Med. 1996 Oct 1; 184(4): 1555–1560.

RNA and DNA expression vectors containing genes for chloramphenicol acetyltransferase,

luciferase, and beta-galactosidase were separately injected into mouse skeletal muscle in vivo.

Protein expression was readily detected in all cases, and no special delivery system was

required for these effects.

In summary, intramuscular injection of plasmid DNA encoding the influenza virus

nucleoprotein results in the induction of NP-specific CTL restricted to the MHC class I

molecules expressed by bone marrow-derived APC

16

17

Fig. 1 Immunogenicity of the

ZIKV PIV vaccine.

Peter Abbink et al. Science 2016;353:1129-1132

Published by AAAS

Fig. 2 Protective efficacy of

the ZIKV PIV vaccine.

Peter Abbink et al. Science 2016;353:1129-1132

Published by AAAS

Fig. 4 Adoptive transfer studies in rhesus monkeys.

Peter Abbink et al. Science 2016;353:1129-1132Published by AAAS

Gene-based vaccines: DNA1,2

CD8+ CTLs

pDNA

Electroporation

Jet injector

Gene gun

Viral vectors

(e.g. Adenovirus,

Poxvirus…)

Options for DNA delivery

Protein

mRNA

Nucleus

1

2

3

4

MHC 1 MHC 2

Illustrative figure based on concepts from:

1. Selby M et al. Expert Opinion on Investigational Drugs 1998 7:12

2. Weiner DB and Nabel GJ 2013; The development of gene-based vectors for immunization; in Vaccines (6th edition) p1232-1242

CD4+ HTLs

22

Rapid development of a DNA vaccine for Zika virus

by Kimberly A. Dowd, Sung-Youl Ko, Kaitlyn M. Morabito, Eun Sung Yang, Rebecca

S. Pelc, Christina R. DeMaso, Leda R. Castilho, Peter Abbink, Michael Boyd, Ramya

Nityanandam, David N. Gordon, John Robert Gallagher, Xuejun Chen, John-Paul

Todd, Yaroslav Tsybovsky, Audray Harris, Yan-Jang S. Huang, Stephen Higgs, Dana

L. Vanlandingham, Hanne Andersen, Mark G. Lewis, Rafael De La Barrera, Kenneth

H. Eckels, Richard G. Jarman, Martha C. Nason, Dan H. Barouch, Mario Roederer,

Wing-Pui Kong, John R. Mascola, Theodore C. Pierson, and Barney S. Graham

Science

Volume ():aai9137

September 22, 2016

Published by AAAS

Fig. 4 Protection from ZIKV challenge correlates with NAb titers present at challenge.

Kimberly A. Dowd et al. Science 2016;science.aai9137

Published by AAAS

Gene-based vaccines: mRNA1

▪ No genomic integration

▪ No anti-vector immunity

▪ Manufacturing simplicity (rapid response to emerging pathogens)

Nucleus

Protein

mRNA

1

2

„naked“ mRNA

MHC 2MHC 1

Figure adapted from:

1. Brito LA. et al. Adv Genet. 2015;89:179-233

Self amplifying mRNA (SAM)

Protein

(+) SAM

Nucleus

(-) SAM

RNA-Polymerase (RP)

(+) SAM

RP ++

mRNA

MHC 1

Gene-based vaccines: mRNA1

Options for delivery

polar/hydrophilic

instable

mRNA

complexed to cationic

carrier(e.g. cationic emulsions;

protamin)

enclosed(e.g. liposomes)

Options for mRNA delivery

Figure adapted from:

1. Brito LA et al. Adv Genet. 2015;89:179-233

Lipid NanoParticle (LNP) / HIV gp140 mRNA (SAM®)

Geall et al. 2012, Proc. Natl. Acad. Sci., 109 (36):14604-9

CD4+ CD8+

Gene-based vaccines: mRNALiposome-carrier strongly enhance immunogenicity

IgG

Controls: 1µg RNA15 µg pDNA

Potential for Zika Vaccine: Preclinical research of a synthetic

mRNA vaccine in public-private partnership (start in 2016)

Self-amplifying mRNA (SAM®) vaccine

Antigen expression

In the vaccinee

Amplification

Immune

response

Manufacture self-

amplifying mRNA

in a cell-free system

Inject self-

amplifying

mRNA

▪ Self-amplifying mRNA to express Zika

virus structural proteins in vaccinee

▪ Transformative technology to simplify

vaccine R&D and manufacturing

▪ SAM® vaccine does not require cell

culture-based manufacturing

▪ Is scalable and flexible

Goals:

▪ Prevent vertical transmission

▪ Prevent Zika virus complications

Version 1, January 5h 2017

29

30

31

Identification of the most promising

candidates can be challenging ....

Trials evaluating multiple candidates over

time against a common group? 1

1. Marston et al. N Engl J Med 2016; 375:1209-12. 2. Beck J. The need to include pregnant women in Zika vaccine trials. The Alantic 6 July 2017.

2

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