2017: Re-emerging and Emerging Infections

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1 2017: Re-emerging and Emerging Infections Richard Whitley, M.D. South Carolina Chapter of the AAP Asheville, North Carolina August 12, 2017

2 Disclosures I am on the Board of Gilead Sciences and will not discuss any of their products I have received remuneration from the NIH and IDSA (Associate Editor JID) I serve on Data Safety and Monitoring Boards for clinical trials sponsored by the NIH, GSK, and Merck My grant support is from NIAID, NIH I do intend to discuss an unapproved/investigative use of a commercial product/device in my presentation.

3 Objectives Appreciate the reappearance of vaccine preventable childhood infections Understand the threat of mosquito borne viral diseases, particularly in the Southern US Know the potential for importation of infectious diseases threats in the US

5 A New World of Infectious Diseases

6 Re-Emerging (Vaccine Preventable) Diseases Pertussis Mumps Measles Don t Forget Influenza

7 PERTUSSIS Highly contagious respiratory infection caused by Bordetella pertussis Outbreaks first described in 16th Century Bordetella pertussis isolated in 1906 Estimated 294,000 deaths worldwide in 2002

8 Increase in Pertussis Cases

U.S. Reported Pertussis Cases, 1990-2010* *2010 data are provisional.

9 U.S. Reported Pertussis Cases, * *2010 data are provisional. CDC, National Notifiable Diseases Surveillance System and Supplemental Pertussis Surveillance System and , passive reports to the Public Health Service

10 Pertussis Cases by Age, San Diego, CA

11 Reported Pertussis-Related Deaths by Age Groups, U.S., Age-group month months months months years years years >18 years Total 77* * Includes one case with unknown age 1 Vitek CR et al. Pediatr Infect Dis J 2003; 22(7): National Notifiable Diseases Surveillance System, CDC, 2009

12 Pertussis Immunization in the United States Whole-cell vaccines / DTwP (1940s) DTaP (1990s) Infants at 2, 4, 6 months (1997) Toddlers at months (1992) Pre-school at 4-6 years (1992) Tdap Adolescents at years (2005) Adults who have not received (2005)

13 MUMPS OUTBREAKS

14 MUMPS 2017

15 CASES OF MEASLES USA (incomplete data set) (in progress)

16 Influenza A Virus Hemagglutinin (H) 16 subtypes (attachment, penetration) Neuraminidase (N) 9 subtypes (release) 8 viral genes (assembly, replication) M2 protein (penetration)

17 Influenza Virus Type of nuclear material Hemagglutinin Neuraminidase A/Fujian/411/2002 (H3N2) Virus type Geographic origin Strain number Year of isolation Virus subtype

18 Influenza Virus Strains Type A moderate to severe illness affects all age groups affects humans and other animals (particularly migratory waterfowl) Type B milder disease primarily affects children humans only

19 Impact of Influenza Approximately 36,000 influenzaassociated deaths during each influenza season Persons 65 years of age and older accounted for more than 90% of deaths The number of deaths and cost to society from influenza is likely to increase as the nation s population ages

20 INFLUENZA ACTIVITY JUNE 2017

21 LRI CLINIC VISITS

22 INFLUENZA

23 INFLUENZA TYPES

25 Recently Approved Influenza Vaccines Quadrivalent live-attenuated influenza vaccine (LAIV4), or Flumist Quadrivalent (MedImmune) Do Not Use Quadrivalent inactivated influenza vaccine (IIV4), or Fluarix Quadrivalent (GSK) Trivalent cell-culture based inactivated influenza vaccine (cciiv3), or Flucelvax (Novartis) Trivalent recombinant hemagglutinin vaccine (RIV3), or FluBlok (Protein Sciences) Quadrivalent inactivated influenza vaccine (IIV4), or Fluzone Quadrivalent (sanofi pasteur).

26 Influenza Antigenic Drift and Antigenic Shift Hemagglutinin Antigenic Shift: Recombinant changes in antigenicity Neuraminidase Antigenic Drift: Mutations result in changes in antigen shape

27 Influenza Vaccine 2017 For , three-component vaccines are recommended to contain: an A/Michigan/45/2015 (H1N1)pdm09-like virus an A/Hong Kong/4801/2014 (H3N2)-like virus a B/Brisbane/60/2008-like (B/Victoria lineage) virus Four-component vaccines, which protect against a second lineage of B viruses, are recommended to be produced using the same viruses recommended for the trivalent vaccines, as well as a B/Phuket/3073/2013-like (B/Yamagata lineage) virus.

28 Information for Healthcare Providers NNII ( VEC ( IAC ( CDC/NIP ( AAP ( AAFP ( IVS ( Vaccine Page ( Every Child by Two ( PKIDS (

29 THE WORLD OF INFECTIOUS DISEASES: IT IS OUR WORLD EMERGING INFECTIONS HIV/AIDS MONKEY POX WEST NILE VIRUS H9N5 HDAI SARS PANDEMIC INFLUENZA MERS EBOLA RE-EMERGING INFECTIONS MEASLES PERTUSIS CHIKUNGUNYA H3N2 INFLUENZA and Zika DENGUE And E68, E71

30 Emerging Infections Respiratory Infections MERS Mosquito Borne Diseases West Nile Chikengunya Zika Contact/Bush Meat Ebola

31 Respiratory Tract Infections: Coronaviruses: SARS/MERS

33 MERS Coronavirus Ongoing 2017 MERS Outbreak

34 MERS Advisory

35 Mosquito Borne Diseases: West Nile Virus Zika Chikungunya Dengue* * For another day

36 West Nile Virus Transmission Cycle

dengue and zika Widely distributed throughout

37 Mosquito Vectors Predominantly Aedes aegypti and Aedes albopictus Same mosquitos that transmit dengue and zika Widely distributed throughout Americas Aggressive daytime biters Aedes aegypti Aedes albopictus

38 Ranges of A. aegypti and A. albopictus in the United States (March 2016). Petersen LR et al. N Engl J Med 2016;374:

39 WNV 2016

40 WNV NEUROINVASIVE DISEASE: 2017

41 WNV Cases in the United States Neuroinvasive Non-Neuroinvasive Total Deaths (%) , , (4.6) All 24,560 24,560 43,937 2,005 (4.6)

42 Zika: 2017

43 Zika Virus Transmission Cycle. Petersen LR et al. N Engl J Med 2016;374:

44 Areas in Which Human Zika Virus Infections Have Been Noted in the Past Decade (March 2016). Petersen LR et al. N Engl J Med 2016;374:

45 Attack Rates for Confirmed and Probable Zika Virus Disease per 1000 Population Duffy MR et al. N Engl J Med 2009;360:

46 Attack Rates for Confirmed and Probable Zika Virus Disease on Yap By Age Duffy MR et al. N Engl J Med 2009;360:

47 Clinical Characteristics of 31 Patients with Confirmed Zika Virus Disease on Yap Island Duffy MR et al. N Engl J Med 2009;360:

48 Cases of ZIKV Infection and the Guillain Barré Syndrome in Colombia. Parra B et al. N Engl J Med 2016;375:

49 US Zika Cases

50 Zika CNS Disease

51 Zika Cases Identified in 2017 Symptomatic Cases: 140 cases All from overseas travel Symptomatic Cases: 510 Cases 470 Puerto Rico Continental US US Territories

52 Microscopic Analysis of Brain Tissue Mlakar J et al. N Engl J Med 2016;374:

53 Human Clinical CHIKV Disease Human infection is characterized by fever (>38.9 C), rash, and polyarthritis % patients develop arthritis: very painful, usually symmetrical, and involves more than one joint Joints most commonly affected include: fingers, wrists, elbows, toes, ankles, and knees. Injured joints are more susceptible to CHIKV polyarthritis Tendon and muscle pain are also common ARTHRITIS LASTS FOR A LONG TIME AFTER INFECTION HAS BEEN CONTROLLED To date there are no approved Vaccines or Therapeutics against CHIKV

54 Chikungunya virus infection Majority (72-97%) of infected people develop clinical symptoms Incubation period is usually 3-7 days (range of 1-12 days) Primary clinical symptoms are fever and polyarthralgia

55 Chikungunya virus in the United States Chikungunya virus is not currently found in the U.S. From , 106 laboratory-confirmed chikungunya cases identified in travelers visiting or returning to U.S., but none triggered a local outbreak in U.S. With outbreaks in Caribbean, number of chikungunya cases among U.S. travelers will likely increase Imported cases may result in virus introduction and local spread in some areas of the U.S.

56 CHIKV Outbreaks: Worldwide Epidemic ECSA A226V ECSA Asian Asian Genotype ECSA A226V Three CHIKV Genotypes: Asian, West African, and East/Central/South African (ECSA)

57 Chikungunya virus in the Americas* Seven Caribbean Countries have reported locally acquired cases > than 1,000 laboratoryconfirmed cases have been reported Virus expected to spread to new areas *As of February 10, 2014

58 Protect from mosquito bites PREVENTION

61 Ebola Virus Disease Centers for Disease Control and Prevention Office of the Director 61

non-segmented, negativestranded RNA virus

Absence of specific treatment or vaccine

outbreaks 2014 West Africa Ebola outbreak

62 Ebola Virus Prototype Viral Hemorrhagic Fever Pathogen Filovirus: enveloped, non-segmented, negativestranded RNA virus Severe disease with high case fatality Absence of specific treatment or vaccine >20 previous Ebola and Marburg virus outbreaks 2014 West Africa Ebola outbreak caused by Zaire ebolavirus species (five known Ebola virus species) 62

63 Ebola Virus Zoonotic virus bats the most likely reservoir, although species unknown Spillover event from infected wild animals (e.g., fruit bats, monkey, duiker) to humans, followed by human-human transmission 63

66 Ebola virus disease (EVD) cumulative incidence* West Africa, January 14, 2015 * Cumulative number of reported EVD cases to WHO 66

67 2014 Ebola Outbreak Reported Cases in Guinea, Liberia, and Sierra Leone This graph shows the cumulative reported cases in Guinea, Liberia, and Sierra Leone provided in WHO situation reports beginning on March 25, 2014 through the most recent situation report on January 14,

68 EVD Cases and Deaths* Reporting Date Total Cases Confirmed Cases Total Deaths Guinea 13 Jan 15 2,825 2,525 1,829 Liberia 12 Jan 15 8,362 3,127 3,556 Sierra Leone 13 Jan 15 10,186 7,825 3,083 Mali 23 Nov United Kingdom 29 Dec Nigeria** 15 Oct Spain** 27 Oct Senegal** 15 Oct United States** 24 Oct TOTAL 21,408 13,510 8,483 Updated case counts available at *Reported by WHO using data from Ministries of Health **The outbreaks of EVD in Senegal, Nigeria, Spain, and the United States have ended. 68

69 Symptoms of Ebola Initial symptoms are nonspecific - may include fever, chills, myalgias, and malaise. Patients can progress to develop gastrointestinal symptoms: severe watery diarrhea, nausea, vomiting, abdominal pain Other symptoms: chest pain, shortness of breath, headache or confusion, conjunctival injection, hiccups, seizures, and cerebral edema Bleeding not universally present but can manifest later as petechiae, ecchymosis/ bruising, or oozing. Frank hemorrhage less common. Some develop diffuse erythematous maculopapular rash that can desquamate. Most common symptoms reported during current outbreak: fever (87%) fatigue (76%) vomiting (68%) diarrhea (66%) loss of appetite (65%) Patients with fatal disease develop more severe clinical signs early during infection and die between days 6-16 of complications (mean of 7.5 days). In non-fatal cases, patients may have fever for several days and improve, around day 6. The case fatality proportion in West Africa is about 71% Source: Centers for Disease Control and Prevention. Accessed Oct. 14, 2014

70 Examples of Hemorrhagic Signs Hematemesis Gingival bleeding Bleeding at IV Site 70

71 Ebola Virus Transmission Virus present in high quantity in blood, body fluids, and excreta of symptomatic EVD-infected patients Opportunities for human-to-human transmission Direct contact (through broken skin or unprotected mucous membranes) with an EVD-infected patient s blood or body fluids Sharps injury (with EVD-contaminated needle or other sharp) Direct contact with the corpse of a person who died of EVD Indirect contact with an EVD-infected patient s blood or body fluids via a contaminated object (soiled linens or used utensils) Ebola can also be transmitted via contact with blood, fluids, or meat of an infected animal Limited evidence that dogs become infected with Ebola virus No reports of dogs or cats becoming sick with or transmitting Ebola 71

72 Human-to-Human Transmission Infected persons are not contagious until onset of symptoms Infectiousness of body fluids (e.g., viral load) increases as patient becomes more ill Remains from deceased infected persons are highly infectious Human-to-human transmission of Ebola virus via inhalation (aerosols) has not been demonstrated 72

74 Patient Recovery Case-fatality rate between 50-70% in the 2014 Ebola outbreak Case-fatality rate is likely much lower with access to intensive care Patients who survive often have signs of clinical improvement by the second week of illness Associated with the development of virus-specific antibodies Antibody with neutralizing activity against Ebola persists greater than 12 years after infection Prolonged convalescence Includes arthralgia, myalgia, abdominal pain, extreme fatigue, and anorexia; many symptoms resolve by 21 months Significant arthralgia and myalgia may persist for >21 months Skin sloughing and hair loss has also been reported References: 1 WHO Ebola Response Team. NEJM 2014; 2 Feldman H & Geisbert TW. Lancet 2011; 3 Ksiazek TG et al. JID 1999; 4 Sanchez A et al. J Virol 2004; 5 Sobarzo A et al. NEJM 2013; and 6 Rowe AK et al. JID

75 Ebola experimental therapeutics Company Agent Mechanism In vivo postexposure efficacy in NHPs* Biocryst BCX4430 Putative inhibitor of EBOV RNA pol (as TP) Broad spectrum antiviral activity 100% protection against related Marburg virus Reference Warren et al, Nature 2014 Mapp Bio/ LeafBio ZMapp (mixture of MoAbs produced in tobacco plant) Inhibition of entry by targeting the GP env protein 100% protection Qui et al, Nature 2014 (in press) Tekmira TKM-Ebola si RNA delivered as lipid nanoparticles Mixture of sirnas targeting L, VP24, and VP35 100% protection Geisbert et al, Lancet 2010 *Tested in cyno/rhesus monkey model with 100% lethality Alios likely identified nucleosides active against Ebola - clinical RSV nuc candidate (AL-8112/8176) might be active against Ebola (Ebola sensitive to nucs active against paramyxoviruses)

76 Lead Compound: Activity Against Ebola GS (parent) GS (prodrug) Compound HMVEC Huh-7 Anti-Ebola Activity; EC 50 [um] Huh-7 (Yield) HeLa HFF-1 Macrophages GS ND > 20 > 20 > 20 GS

77 Thank You

Ebola Virus Transmission

Ebola Virus Transmission Ebola Virus Zoonotic virus bats the most likely reservoir, although species unknown Spillover event from infected wild animals (e.g., fruit bats, monkey, duiker) to humans, followed by human-human transmission