The scope of the Zika pandemic and implications for vaccine development

Transcription

1 The scope of the Zika pandemic and implications for vaccine development Jon Heinrichs, Ph.D. Associate Vice President & Segment Head Early and Pre-Development Projects Zika Vaccine Project Leader

2 Emergence of Zika virus NY Times, April 5, 2016 Newsweek.com Draft for Review 2

3 Isolation of Zika virus jme.oxfordjournals.org Draft for Review 3

4 Worldwide spread of Zika 4

5 Zika virus outbreak to date ZIKV virus first isolated in Zika Valley, Uganda in 1947 from a febrile Rhesus monkey Before 2007 caused only a few mild human cases in Africa and Asia 2007 outbreak in Micronesia: the first Zika outbreak outside Africa and Asia in Yap Island, 919 residents (18%) with mild symptoms 2013 outbreak in French Polynesia ~ 8,750 suspected cases between October 2013 and April cases of Guillain-Barre syndrome (GBS) after the initial Zika infection (encephalitis, meningitis, paraesthesia, facial paralysis and myelitis) In May 2015, Brazil reported first case of Zika and disease has subsequently spread to other parts of Brazil and other Latin American countries In November 2015 the Brazilian Ministry of Health declared a public health emergency in relation to an unusual increase in the number of children born with microcephaly (MC) > 10-fold increase in the incidence of microcephaly By Jan 2016, an estimated 1.3M cases and ~ 3530 MC cases including 46 deaths in 20 states On February 1, 2016 WHO declared Zika a Public Health Emergency of International Concern April 13 CDC concluded Zika is definitive cause of microcephaly April 29- First reported death from Zika in the U.S. (Puerto Rico) 5

6 Areas with Zika active transmission CDC Website, As of April 29,

7 Status of Zika in Brazil States in Brazil investigating microcephaly cases for association with Zika virus infection States in Brazil with confirmed circulation of Zika virus Malone RW, et al. (2016) Zika Virus: Medical Countermeasure Development Challenges. PLoS Negl Trop Dis 10(3): e doi: /journal.pntd

8 Zika virus background ZIKV is a single-stranded, positive-sense RNA virus Member of the genus Flavivirus (family Flaviviridae), which also includes yellow fever virus (YFV), Japanese Encephalitis virus (JEV), West Nile virus (WNV), and the four Dengue viruses (DENV-1 to -4) ZIKV is mostly transmitted by Aedes spp. mosquitoes, and in the case of the Americas more specifically by Aedes aegypti Other transmission routes include sexual transmission, as well as a potential for transmission via blood transfusion Image courtesy of Oloo and Oomen Devika Sirohi et al. Science 2016;science.aaf5316 8

9 Flavivirus genome organization Genomic RNA (positive-polarity, ~ 11 kb) 5 SP genes NS genes 3 Signalase? C prm E NS1 2a 2b NS3 4a 4b NS5 Furin M Viral protease E protein main immunogen eliciting neutralizing antibodies (the generally accepted correlate of protective immunity) T cell epitopes predominantly in E and NS3 proteins 9

10 Phylogeny of members of the genus Flavivirus and ZIKV complete coding region sequences Yap 2007 Cambodia 2010 Thailand 2013 Cook Islands 2014 FP + Americas Viruses 2015, 7(1), ; doi: /v Nuno Rodrigues Faria et al. Science 2016;science.aaf

11 Flavivirus nucleotide sequence alignment Nucleotide sequences of a representative strain of most flaviviruses of importance for public health relevance were selected The full genomes were aligned together and an identity table was generated, showing the percentage of pairwise identity of all aligned sequences There is homology between ZIKV vs DENVs of ~60% (slightly higher than YFV vs DENVs) The most distant sequences are indicated in green whereas closest sequences are shown in red Flavivirus Sequence Alignment Created by Yves Girerd-Gambaz, provided by Bruno Guy 11

12 Zika virus impairs growth in human neurospheres and brain organoids ZIKV infects human neural stem cells induces death in human neurospheres alters morphology and halts the growth of human neurospheres reduces the growth rate of human brain organoids Patricia P. Garcez et al. Science 2016;science.aaf

13 Clinical aspects of Zika disease Zika virus usually produces a mild clinical syndrome: conjunctival hyperemia or bilateral non-purulent conjunctivitis maculo-papular rash low-grade fever (<38.5 C) transient arthritis/arthralgia with possible joint swelling general non-specific symptoms including myalgia, asthenia and headaches Incubation period ranging between 3 and 12 days. Disease symptoms usually mild and short lasting (2 7 days) Zika-associated Guillain-Barré syndrome (GBS) first described during the outbreak in the French Polynesia during Zika-associated microcephaly first described in the context of the current outbreak in Brazil ( ) The link between Zika and GBS has yet to be confirmed 13

14 Zika and microcephaly Primary microcephaly is a severe brain malformation characterized by the reduction of the head circumference Patients display a heterogeneous range of brain impairments, compromising motor, visual, hearing and cognitive functions Microcephaly is associated with decreased neuronal production as a consequence of proliferative defects and death of cortical progenitor cells During pregnancy, the primary etiology of microcephaly varies from genetic mutations to external insults The so-called TORCHS factors (Toxoplasmosis, Rubella, Cytomegalovirus, Herpes virus, Syphilis) are the main congenital infections that compromise brain development in utero The increase in the rate of microcephaly in Brazil has been associated with the recent outbreak of ZIKV. So far, ZIKV has been described in: the placenta and amniotic fluid of microcephalic fetuses in the blood of microcephalic newborns the brain of a microcephalic fetus 14

15 Zika and microcephaly Petersen, et al NEJM 15

16 Microcephaly cases in Brazil: significant increase in per year between 2010 and In 2015, as of 28 November, 1248 suspected cases, of which 509 cases reported between 21 and 28 November

17 Guillain-Barré syndrome cases per 100,000 people per year in US & EU Observed after Campylobacter jejuni, CMV, Epstein-Barr virus, flu A, Mycoplasma pneumoniae, Haemophilus influenzae infections, and after rabies and Flu vaccination, etc Ag mimicry believed to be involved but interplay with host factors not understood Autoimmunity does not arise in most individuals (>99%) exposed to stimulus Willison et al Lancet Feb 29. pii: S (16) [Epub ahead of print] 17

18 Transmission cycles Non-human and human primates are principal vertebrate hosts First isolation (Zika Valley, Uganda, 1947) from a febrile sentinel Rhesus monkey Cercopithecus and Erythrocebus monkeys in Africa (without recognized disease) First reported in humans in 1952 Aedes spp mosquito vectors African species: Ae. africanus, Ae. luteocephalus, Ae. vittatus, Ae. furcifertaylori, Ae. hensilli, Ae. aegypti, etc. Outside of Africa, the principal vector is Ae. aegypti (urban areas), and Ae. albopictus is a potential vector Also can be spread sexually (male to male and male to female) and potentially through contaminated blood Monath, Heinz In: Fields virology, 3 rd Ed, Flaviviruses, pp Grard et al. Zika Virus in Gabon (Central Africa) 2007: A New Threat from Aedes albopictus? PLoS Negl Trop Dis Wong et al. Aedes (Stegomyia) albopictus (Skuse): a potential vector of Zika virus in Singapore. PLoS Negl Trop Dis Aug;7(8):e2348.

19 Global distribution of Aedes aegypti and Aedes albopictus A. aegypti A. albopictus Occurrence Kraemer et al Sci Data 2: Kraemer et al 2015 Elife 4:e

20 Theoretical dispersion of Zika virus Potential for rapid spread to the United States Global spread model integrates Global ecological niche data for Aedes aegypti and albopictus Temperature profiles Characteristics of international travelers Travelers pathway 9.9 million travelers from Brazilian airports 65% to Americas 27% to Europe 5% to Asia Potential dispersion Argentina, Italy and the USA have more than 60% of their populations residing in areas conducive to seasonal zika virus transmission Vaccines are perhaps the best tool to stop the spread of Zika virus and prevent disease. Bogoch. International spread of Zika virus from Brazil, Lancet Draft for Review 20

21 Licensed human flavivirus vaccines Yellow Fever 17D (Sanofi Pasteur, others) Attenuated strain of yellow fever; in use since 1938 Nearly 100% effective, provides life-long immunity Recommended for children over 9 months of age Japanese Encephalitis IXIARO (Valneva, others)- inactivated, Vero cell produced JEV (3 dose series) Live attenuated vaccine- produced in Asia (2 dose) IMOJEV (Sanofi Pasteur) ChimeriVax-JE vaccine, single dose, at least 5 years protection Tick-borne Encephalitis Inactivated vaccines (Baxter, others)- 3 doses Dengue Dengvaxia (Sanofi Pasteur)- Chimerivax-Dengue (4 serotypes) - 3 doses 21

22 Potential vaccine approaches for Zika virus Vaccine Type ZIKV INV (+/- adjuvant) ChimeriVax-ZIKV LAV Maturity of technology Fully established Fully established Dose requirement 2-3 doses for primary immunization 1 dose potential Appropriate for pregnant women during Brazil-like outbreak? Yes Must be assessed Durability of immunity (e.g. for cyclical epidemiology scenario) Periodic boosters needed to maintain immunity Long term (perhaps lifetime) RNA immunization Subunit based on truncated E protein or prm-e VLP Preclinical POC Preclinical POC Unknown Yes Unknown Multiple Yes Short - boosters will be required DNA immunization Early Unknown Yes Unknown Viral vectored Early??? Rational attenuation of ZIKV, incl. using NS mutations Theoretical??? Passively delivered antibody Early Multiple Potentially Short, <3 months 22

23 Sanofi Pasteur s Zika vaccine program 1 STRATEGY Live ChimeriVax approach for broad use Evaluating other technologies in parallel to mitigate risks and accelerate response 2 STATUS Preclinical testing starting 2Q 16 Actively seeking serological diagnostics and animal models Independent.co.uk 3 PARTNERS Important need for international and regional collaborations and partnerships Working with governmental agencies to identify sources of funding

24 Yellow Fever 17D live attenuated vaccine Considered the strongest immunogen in man Single dose provides lifelong immunity Lost the ability to be transmitted by mosquitoes Safe for infants >9 months of age ID 90 <1 log Targets and stimulates antigen-presenting cells Strongly activates innate and adaptive immunity Well known immune correlates (neutralizing antibody) Rapid onset of immunity Protective neutralizing antibody levels in 90% and 99% of vaccinees by day 10 and 30, respectively Can be used to deliver foreign flavivirus proteins 24

25 Construction of ChimeriVax vaccines

26 ChimeriVax vaccines 5 C prm-e Nonstructural 3 YF 17D Dengue-1 PUO-359 (Thailand 1980, human) Dengue-2 PUO-218 (Thailand 1980, human) Dengue-3 PaH881 (Thailand 1988, human) Dengue (Indonesia 1978, human) JE SA (Chinese vaccine) IMOJEV TM WN01 NY99 (veterinary) WN02 mutated NY99 (human) Dengvaxia 26

27 Sanofi Pasteur s dengue vaccine, Dengvaxia The Sanofi Pasteur vaccine is a 4-serotype, recombinant, live, attenuated vaccine. 1,2 Four genetic constructs with 1 for each serotype. Genes encoding prm/e structural proteins from each dengue serotype combined with genes encoding capsid (C) and nonstructural (NS) proteins from YFV 17D vaccine strain. Dengue Dengue 17D 17D yellow Yellow fever fever Combination into a single vaccine. 3 Freeze-dried. Without adjuvant or preservatives. Recombinant Chimeric Virus virus *Vaccine referred to in the literature as Chimeric Yellow Fever 17D-Tetravalent Dengue Vaccine (CYD-TDV). C=capsid; DENV=dengue virus; E=envelope; NS=nonstructural; prm=precursor membrane; YFV 17D=yellow fever vaccine 17D. 1. Guirakhoo, 2001, J Virol. 2. Guirakhoo, 2000, J Virol. 3. Guy, 2011, Vaccine.

28 TWO PHASE III LARGE-SCALE RANDOMIZED EFFICACY STUDIES AND ONE PHASE IIb EFFICACY STUDY OF THE CANDIDATE DENGUE VACCINE INCLUDED >35,000 PARTICIPANTS IN ENDEMIC COUNTRIES 2009: first proof-of-concept phase IIb efficacy study; results published September : 2 large-scale efficacy studies in Asia-Pacific and Latin America; results published in ,3 Phase IIb Efficacy Asia-Pacific (CYD23/57*) Proof-of-concept study 1,4 Country: Thailand Age group: 4 11 years Sample size: 4002 Long-term follow-up: 5 years postdose 3 Phase III Efficacy Asia-Pacific (CYD14) 3 Countries: Thailand, Indonesia, Malaysia, Vietnam, Philippines Age group: 2 14 years Sample size: 10,275 Long-term follow-up: 5 years postdose 3 *CYD57 is the long-term follow up of CYD Sabchareon, 2012, Lancet. 2. Villar, 2015, N Engl J Med. 3. Capeding, 2014, Lancet. 4. Hadinegoro, 2015, N Engl J Med. Phase III Efficacy Latin America (CYD15) 2 Countries: Colombia, Mexico, Honduras, Puerto Rico, Brazil Age group: 9 16 years Sample size: 20,869 Long-term follow-up: 5 years postdose 3

29 SPGLB.DENG CONSISTENT EFFICACY PROFILE IN SUBJECTS 9 16 YEARS OF AGE DURING THE EFFICACY PHASE Key Efficacy Results 25-month active phase* Pooled efficacy analyses 1 Reduction in symptomatic dengue 65.6% (95% CI: ) Reduction in hospitalized dengue 80.8% (95% CI: ) Reduction in severe dengue 93.2% (95% CI: ) For each serotype: DENV-1: 58.4% (95% CI: ) DENV-2: 47.1% (95% CI: ) DENV-3: 73.6% (95% CI: ) DENV-4: 83.2% (95% CI: ) By dengue serostatus: Seropositive: 81.9% (95% CI: ) Seronegative: 52.5% (95% CI: ) *Data come from the 2 pivotal, phase III, large-scale efficacy trials CYD14 and CYD15, which were designed to fully assess efficacy; postdose 1; 1 Full Analysis Set for Efficacy (FASE): all subjects who received at least one injection. dengue hemorrhagic fever, World Health Organization 1997 criteria. CI=confidence interval; DENV=dengue virus. 1.Hadinegoro, 2015, N Engl J Med.

30 Lessons learned from Dengue are pertinent for Zika vaccine considerations Challenge for Dengue vaccine No animal models for disease Dynamic dengue epidemiology Pre-existing immunity to flaviviruses No known immune correlate of protection Theoretical risk of immunopotentation Manufacturing capabilities Lessons Learned for Dengue Need for Clinical studies to down-select candidates Clinical studies performed in multiple endemic settings Importance of collaborations and partnerships in endemic areas Vaccine immunogenicity, safety and efficacy tested in a background of seropositive and seronegative subjects to YF, JEV and DEN Large scale field efficacy trials with lab-confirmed clinical endpoints in 10 endemic countries Large scale safety trials with long-term follow-up Driver for tetravalent formulation Early need to invest in manufacturing infrastructure to have capacity ready for endemic regions immediately after licensure 30

31 Multiple challenges need to be addressed to advance Zika vaccine candidates Examples include: No qualified disease animal models No identified correlate of protective immunity Unknown incidence rates & risk factors for clinical complications Unknown spectrum of clinical complications If GBS association is confirmed, what is the basis of the pathology? Unfolding epidemiology Clinical trial requirements for accelerated registration Need to prevent viremia? Disease endpoints in efficacy trials? The complexities of symptomatic and asymptomatic infection The development of diagnostic assays that avoid cross-reactivity with other flaviviruses Need to prospectively assess Zika/Dengue interactions

32 Timelines for vaccine development First vaccines will likely enter the clinic in late 2016 Inactivated Zika vaccines as well as DNA/RNA vaccines will be available first Initial studies will be in small numbers of healthy individuals to establish safety and immunogenicity Likely to require multiple doses and adjuvants for optimal immunogenicity These vaccines will be best suited to emergency response Vaccines based upon live-attenuated or recombinant technologies will come somewhat later These may provide longer term immunity Clinical studies will be long, costly and difficult to perform Too early to predict when a vaccine will be broadly available 32

33 Conclusions Zika virus has emerged as a global health threat requiring a coordinated response Vaccines, therapeutics and mosquito control are all important parts of a holistic approach to fighting the disease Multiple vaccine technologies need to be evaluated including inactivated, sub-unit and live-attenuated platforms Important lessons can be learned from the development of Dengvaxia and other flavivirus vaccines Sustained investment and partnerships are critically important 33

34 Thank you! 34