The Zika Crisis: Where, What and USG/WHO? Brian R. Moyer BRMoyer & Associates, LLC Bedford, NH

Transcription

1 2016 National Biotechnology Conference, Boston, May 18th The Zika Crisis: Where, What and USG/WHO? Brian R. Moyer BRMoyer & Associates, LLC Bedford, NH

2 2016 National Biotechnology Conference, Boston, May 18th Disclaimer I am a Contractor/SME working in the offices of the Biomedical Advanced Research and Development Authority (BARDA) in HHS under the Asst Secretary for Preparedness and Response (ASPR). I am, presenting here in lieu of a USG representative who could not attend. I am speaking here through HHS public decks and through my own company and NOT as a representative of the US government. In addition, products described herein, or methods used, are not endorsed or advocated by myself, my company, or the US government unless ALREADY APPROVED BY THE FDA

3 2016 National Biotechnology Conference, Boston, May 18th It began in the Zika Forest o The Ziika Forest, better today known as the Zika Forest (~62 acres), is a tropical forest near Entebbe, Uganda o Found while Investigating for Yellow Fever (and another flaviviruses) carrying mosquitos o Zika started hitting Brazil hard about a year ago o The Brazil Zika strain is now circulating in Latin America and the Caribbean and French Polynesia o The Brazil and South Pacific strain(s?) are different from older strains first seen in Africa in the 1940s and 1950s. o Brazilian researchers report evidence the virus may have evolved into a new form that's more likely to damage brain cells and cause birth defects. o Microcephaly is the tip of the iceberg

4 The Zika Virus The Zika virus is a single stranded RNA flavivirus (related to yellow fever, dengue and West Nile Virus (Aedes mosquito vectors) The Zika strain in French Polynesia in 2013 saw an increase in birth defects and is seen as different from the African strain Birth defects are being seen now due to the massive infection rates and the placental load suggests a tissue preference The Zika infection is actually mild in most cases (4 out of 5) Highlighted by a mild but possibly extensive rash and ocular irritation/reddening of the eyes Recovery may be in 7 days but the infected appear to be carriers and can sexually transmit to partners 9 confirmed cases to date (WHO update) Blood transfusion risk National Biotechnology Conference, Boston, May 18th

5 2016 National Biotechnology Conference, Boston, May 18th The Zika Virus Infection rate: 73% (95%CI 68 77) Rates based on serosurvey on Yap Island, 2007 (population 7,391) Symptomatic attack rate among infected: 18% (95%CI 10 27) All age groups affected Adults more likely to present for medical care No severe disease, hospitalizations, or deaths

6 2016 National Biotechnology Conference, Boston, May 18th The Zika Virus Clinical S/S: Zika virus Compared to Dengue and Chikungunya Features Zika Dengue Chikungunya Fever Rash Conjunctivitis Arthralgia Myalgia Headache Hemorrhage Shock - + -

7 2016 National Biotechnology Conference, Boston, May 18th The Zika Virus Diagnostic Testing: Reverse transcriptase-polymerase chain reaction (RT-PCR) for viral RNA in serum collected 7 days after illness onset Serology for IgM and neutralizing antibodies in serum collected 4 days after illness onset Plaque reduction neutralization test (PRNT) for 4-fold rise in virus-specific neutralizing antibodies in paired sera Immunohistochemical (IHC) staining for viral antigens or RT-PCR on fixed tissues

8 The Zika Virus Future Transmission in the Americas? Virus will continue to spread in areas with competent vectors Transmission increasing in Central America, Mexico, and Caribbean Anticipate further spread in Puerto Rico and U.S. Virgin Islands Travel-associated cases will introduce virus to U.S. states Imported cases will result in some local transmission and outbreaks Air conditioning may limit the size and scope of outbreaks Colder temperatures will interrupt and possibly stop further spread Experience from dengue might be predictive From , 1.8 million dengue cases reported per year to PAHO 558 travel-related and 25 locally transmitted cases in U.S. states 2016 National Biotechnology Conference, Boston, May 18th

9 The Aedes Vectors and US Habitat Aedes aegypti and Aedes albopictus Mosquitoes: Geographic Distribution in the United States Aedes aegypti Aedes albopictus Aedes species mosquitoes are efficient vectors for humans Also transmit dengue and chikungunya viruses; aggressive daytime biters Live in and around households Lay eggs in domestic water-holding containers 2016 National Biotechnology Conference, Boston, May 18th

10 The Zika Virus WHO predicts 3 to 4 million new infections in the Americas will be seen in 2016 Viral RNA detectable by rtpcr up to 7 days from the start of symptoms; recovered individuals appear to be carriers IgM Ab test are cross-reactive with other flaviviruses Serious neuroinvasive/neurovirulent sequelae are evident microcephaly, brain calcifications, Guillen-Barre Syndrome, more? Vaccine Development and Approvals: Related to Yellow Fever, JEV, Dengue which have approved vaccines - apparent low cross reactivity Assessment of uncommon adverse reactions (need to detect 1/1000 subjects) Special population needs are becoming increasingly important (children/wocba) 2016 National Biotechnology Conference, Boston, May 18th

11 2016 National Biotechnology Conference, Boston, May 18th WHO Update: May 12 As of May 12 th The WHO reports: Person-to-Person transmission: Nine countries have reported evidence of person-to-person transmission of Zika virus, probably via a sexual route. In the week to 11 May 2016, Grenada is the latest country to report mosquito-borne Zika virus transmission. Microcephaly, and other fetal malformations potentially associated with Zika virus infection or suggestive of congenital infection, have been reported in seven countries or territories. Three cases of microcephaly and other neurological abnormalities are under verification in Venezuela, Honduras and Spain (linked to a stay in Latin America). In the context of Zika virus circulation, 13 countries and territories worldwide have reported an increased incidence of Guillain-Barré syndrome (GBS) and/or laboratory confirmation of a Zika virus infection among GBS cases. Based on research to date, there is now scientific consensus that Zika virus is a cause of microcephaly and GBS.

12 WHO Update: May National Biotechnology Conference, Boston, May 18th

13 WHO Update: May National Biotechnology Conference, Boston, May 18th

14 USG / BARDA Vaccine Development Priorities Collaborate with NIH and DoD to develop inactivated whole Zika virus vaccine Collaborate with industry to advance vaccine platforms that can be used to respond to Zika and other emerging diseases Collaborate with manufacturers in Brazil to build capacity to develop and produce Zika virus vaccines National Biotechnology Conference, Boston, May 18th

15 MCM Development Pipeline Core Service Assistance & Response Infrastructure MCM Stockpiling Support the advanced development of medical countermeasures for CBRN, pandemic influenza, and emerging infectious disease threats Manufacturing Infrastructure BARDA FDA Approvals Highly Dedicated and Talented Team Partnerships National Biotechnology Conference, Boston, May 18th

16 ZIKV Vaccine Landscape National Biotechnology Conference, Boston, May 18th Updated 04/22/2016

17 Epidemic Target population at greatest risk Protection of women of childbearing age and men of similar age Primary health objective is prevention of congenital abnormalities Inter-Epidemic General Population - Healthy adults and children Special populations Pregnant women Establishment of safety in non-pregnant females first No use of live attenuated vaccines Onset of immunity is important Use of established, safe adjuvants only Immunocompromised Geriatric Target Populations for Zika Vaccine Development 2016 National Biotechnology Conference, Boston, May 18th Updated 04/22/2016

18 Zika Virus Vaccine Development Pathway Research and down-selection of platform and antigen design use prior Flavivirus experience Preclinical assessments animal model progress Phase I (safety and immunogenicity) ZIKV naïve patients Flavivirus naïve vs non-naïve Endemic vs non-endemic regions Phase II (safety, immunogenicity, regimen, dose) Human challenge (efficacy, immune correlates) Phase IIb (efficacy, design options) 2016 National Biotechnology Conference, Boston, May 18th Updated 04/22/2016

19 Clinical Trial Design During Epidemics Randomized controlled trials (RCTs) considered gold standard for determining safety and efficacy Provides most reliable data on safety and efficacy of regimens Also provides most efficient means of reaching those answers Feasibility and acceptability demonstrated even in the setting of an outbreak (PREVAIL I) Alternative clinical trial designs have been explored e.g. ring vaccination study in Guinea and immediate vs. deferred vaccination study in Sierra Leone for Ebola 2016 National Biotechnology Conference, Boston, May 18th Updated 04/22/2016

20 Seroconversion Type of immunity, protective titer Clinical Trial Endpoints Confounded by cross reactivity with other Flaviviruses Reduction in incident cases (PCR positivity) Goal is to reduce/prevent viremia to protect fetus Transient viremia in infected people Duration of virus/rna in various tissues an area of active investigation (blood, urine, semen) Urine appears to offer longer duration positivity some groups will use this as an endpoint assay Clinical symptoms/benefit 70% are subclinical/asymptomatic, may underestimate cases Clinical manifestations are predominantly mild Prolonged timeline to determine clinical outcome/benefit 2016 National Biotechnology Conference, Boston, May 18th Updated 04/22/2016

21 The Next Major Challenge: Microcephaly and Neurologic Deficit WHO May 2016 Report: Microcephaly, and other fetal malformations potentially associated with Zika virus infection or suggestive of congenital infection, have been reported in seven countries or territories (Table 3). Two cases, each linked to a stay in Brazil, found Slovenia and the United States One additional US case, linked to a brief stay in Mexico, Guatemala and Belize, Three cases of neurological abnormalities are under verification in Venezuela, Honduras and Spain (linked to a stays in Latin America). 13 countries and territories worldwide have reported an increased incidence of Guillain-Barré syndrome (GBS) associated with Zika virus infection (Table 4). There is scientific consensus that Zika virus is a cause of microcephaly and GBS 2016 National Biotechnology Conference, Boston, May 18th Updated 04/22/2016

22 2016 National Biotechnology Conference, Boston, May 18th Rates of Microcephaly Over Time: the Americas and the Caribbean Comparison of the rates of microcephaly in the Americas and Caribbean from and 2015 Updated as of Epidemiological Week 52 (December 27, 2015 January 2, 2016) Microcephaly rates by state in Brazil (cases per 1,000 live births) Countries Countries with Zika confirmed cases Epi Week Country limits Brazil State Boundaries Data Source: Reported from the IHR National Focal Points and through the Ministry of Health websites. Map Production: PAHO-WHO AD CHA IR ARO Source: Pan American Health Organization, Epidemiological update, 17 January 2016

23 Microcephaly and Neurologic Deficit WHO May 12 Report Countries reporting Guillen-Barre likely associated with Zika Infection: : Brazil, Colombia, Dominican Republic, El Salvador, French Polynesia, Honduras, Suriname, Venezuela (Bolivarian Republic of) 2016 National Biotechnology Conference, Boston, May 18th Updated 04/22/2016

24 Summary of The Crisis Virus will continue to spread in areas with competent vectors Transmission increasing in Central America, Mexico, and Caribbean Anticipate further spread in Puerto Rico and U.S. Virgin Islands Vaccine Development is underway Many platforms Likely to appear for use in late 2016 to mid 2017 We will hear more on this from Dr. Heinrichs shortly The Fetal abnormalities and Neurologic Issues are Emerging From <150 cases per year in Brazil in 2014 to now over 5000 in a few short months we are seeing a major problem emerge Sexual transmission from asymptomatic subjects is possible We will hear more on this from Dr. Schleiss shortly 2016 National Biotechnology Conference, Boston, May 18th

25 Interfacing with BARDA Program description, information, news, announcements Portal to BARDA Register, request a meeting (Tech Watch; jonathan.seals@hhs.gov ) Tech Watch Official announcements and detailed information about all government contract solicitations. Open BARDA BAAs: NIH Federal Funding Opportunities NOT-AI (NIAID) - high-priority ZIKV research areas detailed in the solicitation NOT-HD (NICHD, NINDS, NIDCR, NIAID) - high priority ZIKV research areas PAR (NIAID) rapid assessment of ZIKV complications RFA-AI preclinical development of candidates and platforms 2016 National Biotechnology Conference, Boston, May 18th Updated 04/22/2016