Committee to Advise on Tropical Medicine and Travel - CATMAT. Yellow Fever Update 2018 Manitoba Travel Health Conference Yen-Giang Bui, MD, DTMH

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1 Committee to Advise on Tropical Medicine and Travel - CATMAT Yellow Fever Update 2018 Manitoba Travel Health Conference Yen-Giang Bui, MD, DTMH

2 Conflict of interest None 2

3 Objectives Review CATMAT recommendations on yellow fever vaccine booster doses and use of fractional doses Review epidemiological data of the outbreak in Brazil Discuss the recent cases of yellow fever in international travellers 3

4 CATMAT Yellow Fever Statements 1. Statement for Travellers and Yellow Fever (2013) 2. Interim Canadian Recommendations for the Use of Fractional Dose of Yellow Fever Vaccine during a Vaccine Shortage (2017) 3. Statement on the Use of Booster Doses of Yellow Fever Vaccine (2018) 4

Statement for Travellers and Yellow Fever This statement

Disease characteristics Risk to travellers Preventative measures

5 Statement for Travellers and Yellow Fever This statement provides the following information on yellow fever: Epidemiology Disease characteristics Risk to travellers Preventative measures Vaccination recommendations Current as of January YF_vaccination_africa.png?ua=1

6 USE OF FRACTIONAL DOSE OF YELLOW FEVER VACCINE DURING A VACCINE SHORTAGE 6

7 WHO Fractional Dosing Recommendations Outbreaks in Angola and the DRC put a tremendous strain on vaccine supplies worldwide Urgent need for dose-sparing strategies WHO reviewed evidence on fractional doses of yellow fever vaccine The WHO Strategic Advisory Group of Experts (SAGE) released a statement supporting the use of fractional dosing (0,1 ml instead of 0,5 ml) to control urban outbreaks of yellow fever in June

8 Yellow Fever Vaccine Shortage in Canada - Background SanofiPasteur is the only supplier of yellow fever vaccine in Canada (YF-VAX ) There have been supply issues with this vaccine since 2015 as a result of production problems at the manufacturer s facility in the US Most recently, in 2016, SanofiPasteur announced a shortage of the vaccine that may last until early 2019 In response, CATMAT identified a need to develop guidance to help minimize the impact of the initial vaccine shortage In 2016, CATMAT developed a statement on the use of fractional doses of yellow fever vaccine In 2017, CATMAT published an update to this statement in response to the most recent vaccine shortage 8

9 CATMAT Fractional Dosing Recommendations Based on available data, a fractional dose of yellow fever vaccine (1/5) (0.1 ml instead of 0.5 ml) should be considered protective for one year The use of fractional doses is only recommended during a vaccine shortage when travellers cannot postpone travel and a full dose cannot be obtained A fractional dose does not qualify for the International Certificate of Vaccination or Prophylaxis No recommendation is made regarding repeat fractional dose immunizations 9

10 Data supporting the use of fractional dosing Roukens et al: 1/5 dose given ID vs full dose given SC All subjects developed titres of neutralizing antibody considered to be protective Average age 27 years (range 18 to 70 years) Martins et al: seroconversion and viremia after full dose vs different dilutions given SC No significant difference in immune response down to a dilution of 1:50 All subjects were healthy young males with an average age of 19 years Campi-Azevedo et al (extension of Martins study): serum biomarkers of cellular immunity responses using fractional doses Evidence of protection at dilutions down to 1:50 Consistent findings of equivalency to a full dose across all markers of immunity (serology, viremia and cellular immunity) were found down to a 1:10 dilution 10

11 Potency of yellow fever vaccines The WHO has determined that the minimal concentration of vaccine virus per dose must be 3.0 log 10 IU per 0.5 ml dose or 3000 IU In 2007, WHO published a report on potency of yellow fever vaccines from various manufacturers Concentrations of vaccine viruses varied from 3.3 to 6.4 log 10 IU per dose WHO did not determine a maximal concentration For YF-VAX, the vaccine virus concentration is 4.74 log 10 PFU (equivalent to 4.32 log 10 IU or IU per dose) Source: Sanofi Pasteur, personal communication 11

12 Use of fractional dosing in outbreak control Democratic Republic of Congo Kinshasa: 7.6 million people vaccinated over 10 days Results from a cohort of 716 vaccinees showed 95% seroconversion rate Brazil Source: Mass vaccination campaign started in January 2018 with 23.8 million people expected to get a fractional dose Source: option=com_content&view=article&id=14065%3abrazil-launches-worlds-largest-campaignwith-fractional-dose-yellow-fever-vaccine&catid=1443%3aweb-bulletins&itemid=135&lang=en 12

13 DURATION OF PROTECTION OF A SINGLE DOSE OF YELLOW FEVER VACCINE 13

14 Duration of protection In 2014, the WHO stated that a single dose (0.5 ml) of yellow fever vaccine is sufficient to confer lifelong immunity The Advisory Committee on Immunization Practices in the US made a similar recommendation but specified groups for which booster doses were still recommended CATMAT formed a working group to review the evidence and make recommendations on the need for booster doses of the yellow fever vaccine No efficacy studies performed with YF vaccine so we had to rely on observational and immunogenicity studies Indirect evidence of protection, hence downgrading of recommendation 14

15 CATMAT Evidence Review Epidemiologic evidence Vaccine failures WHO reported 10 cases of yellow fever disease occurring among immunized people ACIP found 18 cases of yellow fever disease occurring among immunized people more than 10 days after receipt of the vaccine During this time, over 540 million vaccine doses were administered Yellow fever epidemics appear to have been stopped by mass immunization and immunized individuals seem to be spared during epidemics Reduction in number of cases with high vaccine coverage Mass immunization in The Gambia in reaching 95% of the population within a 6 month period in response to an outbreak YF vaccine incorporated into the childhood immunizations schedule Coverage rate of children over 80% to the present time The Gambia has only reported a single case involving an unimmunized tourist Senegal, a neighboring country, had lower coverage of its population during this same period of almost 40 years and has experienced several yellow fever outbreaks 15

16 CATMAT Evidence Review Serologic evidence Overall, studies show high rates of seropositivity (ACIP) or seroprotectivity (WHO) in the medium and longer term ACIP s reported seropositivity rates for those immunized 10 years previously are 92% (95% CI 85% 96%) and for those vaccinated 20 years previously, 80% (95% CI 74% 86%) Limited data on very long-term immunity 16

17 CATMAT Evidence Review Ancillary evidence Booster doses of yellow fever vaccine do not often lead to dramatic increases in antibody titres Possibility that innate and cell-mediated immunity generated by the vaccine are more important for long-lasting protection against natural infection than antibodies Furthermore, chronic persistent infection with the vaccine virus or storage of antigen in vivo, possibly in follicular dendritic cells, may also explain the durability of the human immune response 17

18 CATMAT Booster Dose Recommendations Insufficient information exists to confidently state the duration of protection afforded by a single dose of yellow fever vaccine Notwithstanding the paucity of evidence for lifelong protection from one dose, CATMAT recommends that no booster dose of yellow fever vaccine be routinely given except for three special groups: Individuals in whom response to prior vaccination may be diminished Individuals at particularly high risk of exposure Individuals with regular and ongoing risk of exposure 18

19 CATMAT Booster Dose Recommendations Considerations which support a recommendation AGAINST repeat doses of yellow fever vaccine Yellow fever is extremely rare in travellers Epidemiologic and serologic evidence, albeit very low quality, that the vaccine confers long-term protection from a single dose The possibility that innate and cellular immune responses play a role in long term protection The rarity of documented vaccine failures There are known adverse events of the vaccine which can be serious, including the very rare risk of yellow fever vaccine-associated neurologic disease in previously immunized individuals 19

20 Recommendations for Yellow Fever Vaccine Booster in Special Groups 20

21 Recommendations for Yellow Fever Vaccine Booster in Special Groups Group Individuals at particularly high risk of exposure Individuals travelling to an area experiencing an epidemic or major outbreak Individuals travelling frequently or for prolonged periods to areas of high endemicity particularly West Africa Recommendation Consider a one-time booster dose of yellow fever vaccine prior to such travel if 10 years have elapsed since the primary dose and no previous booster doses administered Individuals with regular and ongoing risk of exposure Laboratory personnel working with live yellow fever virus A booster is recommended every 10 years unless measured neutralizing antibody titre to yellow fever virus confirms ongoing protection 21

22 Duration of protection in young children WHO concluded that children may not develop an immunologic response as effectively as adults or may lose immunity more rapidly Some of these studies have methodologic limitations or confounding factors ACIP does not recommend booster doses for immunocompetent children CATMAT does not make specific recommendations for a booster dose in young children More research is needed to determine the duration of immunity in this group Individual assessment of risks and benefits should be done when considering re-immunization of children who received their first dose prior to one year of age 22

23 DURATION OF VALIDITY OF THE ICVP 23

24 Amendement to the IHR In 2014, the WHO adopted an amendment to Annex 7 of the IHR stating that the duration of validity of the ICVP is lifelong and all valid ICVPs must be accepted, even those that are more than 10 years old As of 11 July 2016, revaccination or a booster dose of yellow fever vaccine cannot be required of international travellers as a condition of entry into a country 24

25 Challenges for Travel Health practitioners Implementation of the amendment has been erratic Anecdotal reports of travellers being denied entry with «old» certificates, even with WHO s accompanying document Changes made to entry requirements by some countries without prior notice Some African countries have changed their requirements Require the ICVP only for travellers from at risk countries, leading to increased vaccine refusals, esp in VFRs 25

26 OUTBREAK OF YELLOW FEVER IN BRAZIL 26

27 Epidemiology Since 2016, Brazil has been battling an outbreak of yellow fever From July 2016 to June 2017: 779 human cases of yellow fever and 262 deaths From July 1 st 2017 to March 27 th 2018: 4414 suspect cases, 1131 confirmed cases and 338 deaths YF virus circulates in metropolitan regions compared to : explains higher number of cases Population at risk more than 35 million Incidence lower 3/ vs 6.6/ in

28 Epidemiology On April 2 nd 2018, YF reached the north coast of Sao Paolo 2 monkeys reported dead from YF: 1 in Ubatuba Forest and 1 in gatedcommunity of Juquehy, São Sebastião 1 human case under investigation (Serra do Mar Park) Intensification of the vaccination campaign Vaccine coverage in São Sebastião estimated at 47% 28

29 Confirmed human cases of yellow fever , Brazil RRA%20UPDATE%203-Yellow%20fever-Brazil-rev1.pdf 29

30 Distribution of confirmed YF cases, Brazil

Distribution of epizootics, Sao Paolo state, 2016-2018 http://www.paho.

31 Distribution of epizootics, Sao Paolo state,

Confirmed human cases and epizootics, Brazil, Jan-March 2018 http://www.paho.

32 Confirmed human cases and epizootics, Brazil, Jan-March

Confirmed epizootics and regions at risk, Brazil http://www.paho.

33 Confirmed epizootics and regions at risk, Brazil 33

34 Entomological investigations During the outbreak in some of the affected states isolated Haemagogus mosquitoes positive for yellow fever virus No evidence of transmission by Aedes aegypti was found In January 2018, health authorities in Brazil reported that YF virus had been detected in Aedes albopictus mosquitoes captured in rural areas of Itue ta and Alvarenga municipalities in Minas Gerais State in 2017 Further investigation is needed to determine the significance of this finding to confirm vector competence and vector capacity in transmitting yellow fever 34

35 Vaccination campaigns Mass vaccination campaigns started in January 2018 and are still ongoing in Sa o Paulo, Bahia and Rio de Janeiro states As of March 13th 2018, 17.5 million people have been vaccinated Vaccination coverages 69%, 95% and 54% in Rio de Janeiro, Sa o Paulo and Bahia states, respectively On March 20th 2018, the Brazilian Minister of Health announced that the whole country should be vaccinated, starting with regions at risk and gradually covering all other areas over the next year Goal: 79 million people vaccinated by

36 Vaccine recommendations for travellers to Brazil -fever-brazil 36

37 Cases of yellow fever in international travellers ECDC reported four cases in European travellers between August 2016 and acquired in Bolivia 1 Suriname 2 Peru Between 1999 and August 2016: 3 reported cases acquired in Africa Increased transmission of YF virus in South America since last 2 years 37

38 Cases of yellow fever in international travellers MMWR reported in March 2018 that since Jan 2018, 10 cases of yellow fever in travellers from Europe and South America who visited Brazil, all non vaccinated Another case was reported on ProMed early March 2018 in a German tourist 9 cases acquired YF on Ilha Grande (near Rio de Janeiro) and 4 died 1 case visited Minas Gerais and 1 visited Sao Paolo state Majority short trips (1-4 weeks) 38

Probable place of infection-european travellers https://www.ecdc.europa.

39 Probable place of infection-european travellers RRA%20UPDATE%203-Yellow%20fever-Brazil-rev1.pdf 39

40 Ilha Grande, Brazil 40

41 Ilha Grande, Brazil 41

42 Yellow fever in South America Cyclical activity Alternate between endemicity and epidemics 3-7 years cycles linked to epizootics in non-human primates Last epidemic was in Long periods without evidence of transmission French Guyana no case since 1902, 1 case reported in 1998 Suriname no case since 1972, 1 case reported in Dutch tourist in

43 Key points Period of increased YF virus activity in South America Expansion of the virus into metropolitan areas in Brazil Many countries, including Brazil, do not require the YF vaccine as a condition for entry, however there is a risk of contracting the disease Very important to adequately counsel travellers of the distinction between entry requirements and vaccine recommendations Some countries can decide to modify their entry requirements without prior notice to WHO Always a good idea to double check countries requirements at 43

Thank you! Questions? Contact Information: CATMAT.Secretariat@phac-aspc.gc.ca https://www.canada.

44 Thank you! Questions? Contact Information: 44

Are 10-year booster doses of yellow fever vaccine necessary? Peter Teitelbaum, MD Committee to Advise on Tropical Medicine and Travel (CATMAT)

Are 10-year booster doses of yellow fever vaccine necessary? Peter Teitelbaum, MD Committee to Advise on Tropical Medicine and Travel (CATMAT) Disclosure of Potential for Conflict of Interest Peter Teitelbaum,