Yellow Fever: Background on Disease, Vaccine, and Recent Vaccine Developments

Transcription

1 Yellow Fever: Background on Disease, Vaccine, and Recent Vaccine Developments J. Erin Staples, MD, PhD Arboviral Disease Branch, Centers for Disease Control and Prevention, Fort Collins, CO, USA Colorado Coalition of Travel Health Professionals April 10, 2014 National Center for Emerging and Zoonotic Infectious Diseases Division of Vector-borne Diseases

2 Yellow Fever (YF) Disease 2

3 YF Overview Caused by YF virus (Flavivirus) Virus transmitted predominantly by Aedes mosquitoes Endemic in equatorial Africa and South America Estimated 200,000 cases and 30,000 deaths annually 3

4 YF Virus Transmission Cycles Jungle/ Sylvatic Intermediate/ Savannah Urban Africa only Aedes africanus Haemagogus or Sabethes spp. Semi-domestic Aedes spp. Aedes aegypti 4

5 Worldwide Distribution of YF Jentes ES, et al. Lancet Infect Dis 2011; 11:

6 YF Clinical Presentation Death Detected by surveillance Not detected by surveillance Fever + Jaundice or Hemorrhage Fever Asymptomatic Incubation period of 2-6 days 6

7 Diagnostic Testing for YF Serum for YF-specific IgM antibodies Confirmatory (plaque reduction neutralization testing, PRNT) testing needed due to cross-reactive flaviviral antibodies (e.g., dengue, WNV) Acute samples often positive for virus by viral isolation or viral RNA detection through RT-PCR Post-mortem samples should be obtained Frozen viral isolation and RNA detection Fixed IHC staining 7

8 YF Treatment, Prevention, and Control Treatment No specific anti-viral treatment Supportive therapy Prevention and control Mosquito control Vaccination 8

9 Mosquito Prevention and Control Use air conditioning or window/door screens Rest/sleep under bed nets Use mosquito repellents on exposed skin DEET, Picaridin, IR3535, Oil of lemon eucalyptus Apply sunscreen first then repellent Wear long-sleeved shirts and long pants Treat clothing with permethrin or purchase pretreated clothing 9

10 YF Vaccine Background 10

11 Development of YF Vaccine Asibi strain obtained in 1927 Passed >200 times to develop live attenuated viral vaccine, 17D vaccine Two distinct substrains used in vaccines today* 17DD produced in Brazil 17D-204 used by manufacturers outside Brazil All vaccines produced in embryonated eggs but differ in substrain, passage level, and stabilizers *17D-213 substrain, a derivative of 17D-204, also exists as reference stock maintained by WHO for new manufacturers or source of emergency production 11

12 Currently Available YF Vaccines WHO prequalified Bio-Manguinhos, 17-DD, Brazil sanofi pasteur, Stamaril, 17D-204, France Pasteur Institute Dakar, 17D-204, Senegal Chumakov Institute, 17D-204, Russian Federation Local use sanofi pasteur, YF-Vax, 17D-204, USA (used in USA and Canada) China National Biotech Group, 17D-204, China 12

13 Immunogenicity of YF Vaccine No placebo controlled studies of efficacy Incidence of YF among lab workers and in endemic areas declined after vaccination began >99% of vaccinated persons develop antibody response at 28 days post vaccination 13

14 Common Adverse Events Fever, headache, backache 3-7 days after vaccination: 5%-15% Injection site inflammation 1-5 days after vaccination: 1%-30% 14

15 Serious Adverse Events (SAEs) and Rates for YF Vaccine Overall reporting rate for SAEs in U.S. population is 4.7 per 100,000 doses distributed* Three primary SAEs Anaphylaxis per 100,000 doses Neurologic disease per 100,000 doses Viscerotropic disease per 100,000 doses Lindsey et al. Vaccine 2008; 26: ; Khromava et al. Vaccine 2005; 23: ; Kelso et al. J. Allergy Clin Immunol. 103:

16 YF Vaccine and Anaphylaxis Most commonly urticaria with respiratory symptoms (e.g., dyspnea, throat tightness, wheezing) Known risk factor is allergy to vaccine component (e.g., eggs, chicken proteins, gelatin) Rarely fatal Seen predominantly after initial vaccination 16

17 YF Vaccine-Associated Neurologic Disease Spectrum of illnesses due to either direct viral invasion of CNS or autoimmune mediated Most common presentation is meningoencephalitis Others: GBS, ADEM, bulbar palsy, Bell s palsy Absolute number of cases is unknown Onset median 11 days (2-28 days) post vaccination Rarely fatal with five death noted Reported predominantly after initial vaccination 17

18 YF Vaccine-Associated Viscerotropic Disease Severe illness similar to wild-type disease with vaccine virus proliferating in multiple organs Over 65 cases since first recognized in 2001 Onset median 3 days (1-8 days) post vaccination Tends to affect younger females and older males though age range between sexes is similar 63% case-fatality rate Confirmed cases only reported after first vaccine dose 18

19 Indications and Recommendations for Use of YF vaccine 19

20 Current ACIP YF Vaccine Recommendations Last work group formed in 2008 to update previous recommendations Update YF epidemiology Include information on IHR (2005) Update vaccine safety data Add/improve wording for vaccine precautions and contraindications Updated recommendations published July

21 ACIP Recommendations for Use of YF Vaccine in Travelers Recommended for persons aged 9 months who are traveling to or living in areas at risk for YF virus transmission Because of risk of serious adverse events, healthcare providers should vaccinate only persons who are at risk for exposure to YF virus or require proof of vaccination for country entry Single subcutaneous dose; IHRs require revaccination at intervals of 10 years to boost antibody titers 21

22 Contraindications and Precautions to YF Vaccine Administration Contraindications Allergy to vaccine component* Age <6 months Symptomatic HIV infection or CD4+ counts <200/mm 3 Thymus disorder Primary immunodeficiencies Malignant neoplasms Transplantation Immunosuppressive and immunomodulatory therapies Precautions Age 6-8 months Age 60 years Asymptomatic HIV and CD4+ counts /mm 3 Pregnancy Breastfeeding * Desensitization can be performed under direct supervision of physician experienced in management of anaphylaxis 22

23 Age and Rates of Serious Adverse Events Infants and older adults have increased rates of yellow fever vaccine-associated SAEs YEL-AND* 1 Data derived from before YF vaccine universally contraindicated in infants < 6 mo; 2 As reported to VAERS Ref: Lindsey et al. Vaccine 2008; 26: YEL-AVD* < 6 months old years old years old All ages *Per 100,000 doses 23

24 HIV Infection and YF Vaccine No large prospective study performed in HIVinfected persons Small studies and case reports of ~550 HIVinfected persons receiving YF vaccine One YEL-AND death in patient with CD4 count of 108 No other serious adverse events reported Studies included ~20 persons CD4 counts < 200 Variable seroconversion (17% - 100%) Receveur et al. Clin Infect Dis. 2000;31:E7; Kengakul et al. J Med Assoc Thai. 2002;85:131; Wilson et al. Ann Int Med. 1991;114:582; Tattevin et al. AIDS. 2004;18:825; Pistone et al. BEH them. 2007;25:238; Ho et al. AIDS Pt Care STDS. 2008;22:65; Veit et al. Clin Infect Dis. 2009;48:659; Goujon et al. 1995, 4 th Conf travel Med; Sibailly et al. PIDJ. 1997;16:1177. Sidibe et al. Trans Roy Soc Trop Med Hyg. 2012;106:

25 Thymus Disorders and YF vaccine Of initial 23 YEL-AVD cases, 4 (17%) occurred in persons who had thymectomies performed for thymomas 1 In 2003, thymus disorder was added to the YF vaccine package insert as contraindication No evidence of immune dysfunction or increased risk of YF vaccine-associated SAEs following incidental surgical removal or distant radiation therapy 1 Eidex RB. Lancet 2004; 364:

26 Other Immunodeficiencies and YF vaccine No data on use of YF vaccine in persons with other immunodeficiencies Primary immunodeficiencies, malignant neoplasms, and transplantation are presumed to increase the risk of YF vaccine-associated SAEs 26

27 Immunosuppressive or Immunomodulatory Therapies and YF Vaccine Minimal to no data on use of YF vaccine in persons receiving immune suppressive / modulatory therapies Increase in number and use of immunomodulatory drugs TNF-α inhibitors (e.g., etanercept) IL-1 blocking agents (e.g., anakinra) Monoclonal antibodies (e.g., rituximab, alemtuzumab) Most immune suppressive / modulatory drugs are presumed to increase the risk of YF vaccine SAEs Package inserts of most immunomodulatory drugs state that the use of live viral vaccines is contraindicated 27

28 Pregnancy and YF Vaccine No prospective trial in pregnant women Limited data suggest no increased rates of Major malformation in infants 1 Spontaneous abortions 2 Limited and conflicting immunogenicity data with seroconversion rates between 39% and 98% 2,3 1 Cavalcanti et al. Trop Med Int Health 2007; 12: ; 2 Suzano et al. Vaccine 2006; 24: ; 3 Nasidi et al. Trans Roy Soc Trop Med Hyg 1993;87:

29 Breastfeeding and YF Vaccination Three YEL-AND cases recognized in breastfed infants whose mothers had received YF vaccine* Infants were <1 mo of age and exclusively breastfed All developed encephalitis YF vaccine virus recovered from CSF in one infant; YF- IgM antibodies identified in CSF in two others No breast milk available for testing Overall risk of transmission of YF vaccine virus through breastfeeding is unknown *CDC. MMWR. 2010; 59: 130-3; Kuhn et al. CMAJ. 2011; 183: E243-5; Traiber et al. J Pediatr (Rio J). 2011; 87:

30 Requirements versus Recommendations for YF Vaccine 30

31 Yellow Fever Vaccine Requirements and International Health Regulations (IHR) Most endemic countries require proof of vaccination for all travelers from endemic areas Certain countries with vectors but without disease require proof of vaccination for all travelers from endemic areas and some non-endemic areas United States has no vaccine requirement for entry Only vaccine covered under IHR (2005) Can detain traveler without proof of vaccination for 6 days (incubation period) 31

32 YF Vaccine Recommendations Advice given to prevent YF infections in travelers Based on best available YF epidemiologic data Categorized as endemic, transitional, low, and no risk In 2011, CDC and WHO harmonized recommendations Endemic and transitional areas Vaccine recommended Low potential Vaccine generally not recommended No risk No vaccination 32

33 Recommendations for South America 33

34 Vaccine Recommendations for Africa 34

35 Recommendations versus Requirements Requirements subject to change at any time Recommendations subject to change depending on new epidemiologic data Detailed list of vaccine recommendations versus requirements for each country available at: Yellow Book ( WHO s Green Book ( Always consider transit routes when assessing recommendations versus requirements 35

36 Proof of YF Vaccination Documented on International Certificate of Vaccination or Prophylaxis (ICVP) Medical contraindications need to be noted in respective section 36

37 Medical Waivers for YF Vaccination If YF vaccine is medically contraindicated Complete Medical Contraindication to Vaccination Give traveler signed, dated, and stamped exemption letter on physician's letterhead stationary Inform traveler of increased risk of YF with nonvaccination Counsel traveler about mosquito prevention measures Issuance of waiver does not guarantee its acceptance by destination country Traveler should consider contacting destination country embassy for further guidance 37

38 Risk of Medical Waivers Unvaccinated travelers going to endemic areas could be at significant risk of contracting YF 8 fatal cases of YF reported in unvaccinated travelers to endemic countries Options for travelers with contraindications or precautions to YF vaccine Get YF vaccination and travel to endemic area risk Get waiver and travel to endemic area risk No vaccine and no travel to endemic area least risk 38

39 Risk Benefit Assessment for YF vaccine Risk of acquiring yellow fever for travelers Africa: Estimated 50 disease cases per 100,000 per 2 week stay during peak transmission from Jul Oct Average annual risk closer to 10 per 100,000 per 2 week (lower risk during off season ) South America: Estimated 5 disease cases per 100,000 per 2 week stay Risk of serious adverse event >70 years old Any serious event: 12.6 per 100,000 doses YEL-AVD: 2.3 per 100,000 doses 39

40 Recent Vaccine Developments 40

41 WHO YF Vaccine Recommendations SAGE formed YF vaccine work group in 2011 Need for booster dose every 10 years to maintain protection against YF Safety of YF vaccine in selected special populations Co-administration of YF and other vaccines Updated position paper published in July

42 Updated SAGE YF Vaccine Booster Dose Recommendations A single dose of YF vaccine is sufficient to confer sustained life-long protective immunity against YF disease; a booster dose is not necessary. 42

43 Status of Booster Doses for US Travelers ACIP work group began discussing need for booster doses in 2013 Use GRADE approach to assess YF vaccine data Long-term immunogenicity Vaccine failures Serious adverse events Recommendations of work group regarding booster doses to be presented to ACIP in 2014 Until recommendations are updated, booster doses still recommended for US travelers 43

44 YF Vaccine Shortage Sole supplier of YF vaccine in US announced shortage of single dose vials in late 2013 Reason for shortage unknown Vaccine needs several months to be produced Need sterile fertilized eggs Multi-dose vials were not impact but distribution limited to prevent critical shortages Notice of shortage posted on CDC travel health website 44

45 45

46 Updated YF Disease and Vaccine Information for Travelers 46

47 Resources CDC s Yellow fever website ( ACIP YF vaccine recommendations ( CDC s Yellow Book ( CDC s Travel Health Website ( CDC s Yellow Fever Vaccine Course ( CE eligible WHO s Green Book ( 47

48 Questions and Discussion The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. 48