2017: Re-emerging and

Emerging Infections

Richard Whitley, M.D.

South Carolina Chapter of the AAP

Asheville, North Carolina

August 12, 2017

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.

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

A New World of Infectious

Diseases

Re-Emerging (Vaccine Preventable)

Diseases

• Pertussis

• Mumps

• Measles

• Don’t Forget Influenza

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

Increase in Pertussis Cases

U.S. Reported Pertussis Cases,

1990-2010**2010 data are provisional.

CDC, National Notifiable Diseases Surveillance System and Supplemental Pertussis Surveillance System and 1922-1949,

passive reports to the Public Health Service

Pertussis Cases by Age,

San Diego, CA

Reported Pertussis-Related Deaths

by Age Groups, U.S., 1980-2009

Age-group 1980-19891 1990-19991 2000-20092

0-1 month 38 68 152

2-3 months 11 16 23

4-5 months 5 5 2

6-11 months 7 4 1

1-4 years 13 2 2

5-10 years 1 6 3

11-18 years 0 0 3

>18 years 1 2 8

Total 77* 103 194

1 Vitek CR et al. Pediatr Infect Dis J 2003; 22(7):628-34.

2 National Notifiable Diseases Surveillance System, CDC, 2009

* Includes one case with unknown age

Pertussis Immunization

in the United States• Whole-cell vaccines / DTwP (1940s)

• DTaP (1990s)

– Infants at 2, 4, 6 months (1997)

– Toddlers at 15-18 months (1992)

– Pre-school at 4-6 years (1992)

• Tdap

– Adolescents at 11-12 years (2005)

– Adults who have not received (2005)

MUMPS OUTBREAKS

MUMPS 2017

CASES OF MEASLES USA

• 2010 63

• 2011 220

• 2012 55

• 2013 187

• 2014 667

• 2015 188

• 2016 70 (incomplete data set)

• 2017 108 (in progress)

Hemagglutinin (H) – 16 subtypes

(attachment, penetration)

Neuraminidase (N) – 9 subtypes

(release)

8 viral genes

(assembly, replication)

M2 protein

(penetration)

Influenza A Virus

Influenza Virus

A/Fujian/411/2002 (H3N2)

Neuraminidase

Hemagglutinin

Type of nuclear

material

Virus

type

Geographic

origin

Strain

number

Year of

isolation

Virus

subtype

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

Impact of Influenza

• Approximately 36,000 influenza-

associated 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

INFLUENZA ACTIVITY JUNE

2017

LRI CLINIC VISITS 2016-1017

INFLUENZA 2016-2017

INFLUENZA TYPES 2016-2017

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).

Influenza

Antigenic Drift and Antigenic

ShiftHemagglutinin

Neuraminidase

Antigenic Shift:

Recombinant

changes in

antigenicity

Antigenic Drift:

Mutations result

in changes in

antigen shape

Influenza Vaccine 2017

• For 2017-2018, 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.

Information for Healthcare

Providers• NNII (www.immunizationinfo.org)

• VEC (www.vaccine.chop.edu)

• IAC (www.immunize.org)

• CDC/NIP (www.cdc.gov/nip)

• AAP (www.aap.org)

• AAFP (www.aafp.org/)

• IVS (www.vaccinesafety.edu)

• Vaccine Page (www.vaccines.org)

• Every Child by Two (www.ecbt.org)

• PKIDS (www.pkids.org/)

THE WORLD OF INFECTIOUS DISEASES: IT IS OUR

WORLD

RE-EMERGING

INFECTIONS

EMERGINGINFECTIONS

20152010200520001995199019851980

HIV/AIDSMONKEY

POX

WESTNILE VIRUS SARS

PANDEMICINFLUENZA

MERS

EBOLA

CHIKUNGUNYA

DENGUEAnd E68, E71

H3N2INFLUENZA

and Zika

H9N5HDAI

MEASLES

PERTUSIS

Emerging Infections

• Respiratory Infections

– MERS

• Mosquito Borne Diseases

– West Nile

– Chikengunya

– Zika

• Contact/Bush Meat

– Ebola

Respiratory Tract Infections:

Coronaviruses: SARS/MERS

MERS CoronavirusOngoing 2017 MERS Outbreak

MERS Advisory

Mosquito Borne Diseases:

West Nile Virus

Zika

Chikungunya

Dengue*

* For another day

West Nile Virus Transmission

Cycle

Mosquito Vectors

• Predominantly Aedes aegypti and Aedes

albopictus

• Same mosquitos that transmit dengue and

zika

• Widely distributed throughout Americas

• Aggressive daytime bitersAedes aegypti Aedes albopictus

Ranges of A. aegypti and A. albopictus in the United States (March 2016).

Petersen LR et al. N Engl J Med 2016;374:1552-1563

WNV 2016

WNV NEUROINVASIVE

DISEASE: 2017

WNV Cases in the United

States

1999-2017

Neuroinvasive Non-Neuroinvasive Total Deaths (%)

2016 1,140 898 2,038 94 (4.6)

All 24,560 24,560 43,937 2,005 (4.6)

Zika: 2017

Zika Virus Transmission Cycle.

Petersen LR et al. N Engl J Med 2016;374:1552-1563

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;374:1552-1563

Attack Rates for Confirmed and Probable Zika Virus Disease per 1000 Population

Duffy MR et al. N Engl J Med 2009;360:2536-2543

Attack Rates for Confirmed and Probable Zika Virus Disease on Yap By Age

Duffy MR et al. N Engl J Med 2009;360:2536-2543

Clinical Characteristics of 31 Patients with Confirmed Zika Virus Disease on Yap Island

Duffy MR et al. N Engl J Med 2009;360:2536-2543

Cases of ZIKV Infection and the Guillain–Barré Syndrome in Colombia.

Parra B et al. N Engl J Med 2016;375:1513-1523

US Zika Cases

Zika CNS Disease

Zika Cases Identified in 2017

• Symptomatic Cases: Continental US

– 140 cases

– All from overseas travel

• Symptomatic Cases: US Territories

– 510 Cases

• 470 Puerto Rico

Microscopic Analysis of Brain Tissue

Mlakar J et al. N Engl J Med 2016;374:951-958

Human Clinical CHIKV Disease• Human infection is characterized by fever

(>38.9°C), rash, and polyarthritis

• 90-100% 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

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

Chikungunya virus in the United

States• Chikungunya virus is not currently found in the U.S.

• From 2006-2009, 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.

CHIKV Outbreaks: Worldwide Epidemic

Three CHIKV Genotypes: Asian, West African, and East/Central/South African (ECSA)

Asian Genotype

ECSAA226V

ECSA

Asian

ECSAA226V

Chikungunya virus in the Americas*

• Seven Caribbean Countries

have reported locally acquired

cases

• > than 1,000 laboratory-

confirmed cases have been

reported

• Virus expected to spread to

new areas

*As of February 10, 2014

PREVENTION

Protect from mosquito bites

Ebola Virus Disease

Centers for Disease Control and Prevention

Office of the Director61

Ebola Virus

Prototype Viral Hemorrhagic

Fever Pathogen

Filovirus: enveloped,

non-segmented, negative-

stranded 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

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

Ebola virus disease (EVD) cumulative incidence* —

West Africa, January 14, 2015

* Cumulative number of reported EVD cases to WHO

66

2014 Ebola OutbreakReported 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, 2015.

67

EVD Cases and Deaths*

Updated case counts available at http://www.cdc.gov/vhf/ebola/outbreaks/2014-west-africa/case-counts.html.

*Reported by WHO using data from Ministries of Health

**The outbreaks of EVD in Senegal, Nigeria, Spain, and the United States have ended.

68

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 14 8 7 6

United Kingdom 29 Dec 14 1 1 0

Nigeria** 15 Oct 14 20 19 8

Spain** 27 Oct 14 1 1 0

Senegal** 15 Oct 14 1 1 0

United States** 24 Oct 14 4 4 1

TOTAL 21,408 13,510 8,483

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. http://www.cdc.gov/vhf/ebola/hcp/clinician-information-us-healthcare-settings.html Accessed Oct. 14, 2014

Examples of Hemorrhagic Signs

Bleeding at IV Site

Hematemesis

Gingival bleeding

70

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

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

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 reportedReferences: 1WHO Ebola Response Team. NEJM 2014; 2Feldman H & Geisbert TW. Lancet 2011; 3Ksiazek TG et al. JID

1999; 4Sanchez A et al. J Virol 2004; 5Sobarzo A et al. NEJM 2013; and 6Rowe AK et al. JID 1999.

74

Ebola experimental therapeutics

Company Agent Mechanism In vivo postexposure

efficacy in NHPs*

Reference

Biocryst BCX4430 Putative inhibitor

of EBOV RNA

pol (as TP)

Broad spectrum

antiviral activity

100% protection

against related

Marburg virus

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)

GS-466547

(prodrug)

Lead Compound: Activity

Against Ebola

Compound

Anti-Ebola Activity; EC50 [uM]

HMVEC Huh-7Huh-7

(Yield)HeLa HFF-1 Macrophages

GS-441524 0.77 1.5 ND > 20 > 20 > 20

GS-466547 0.12 0.09 0.01 0.24 0.23 0.07

GS-441524

(parent)

Thank You