11

Hepatitis E VaccineHepatitis E VaccineClinical ExperienceClinical Experience

Mrigendra P. Shrestha

22

Hepatitis E in NepalHepatitis E in Nepal

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Hepatitis E in NepalHepatitis E in Nepal

Most common type of acute viral hepatitisMost common type of acute viral hepatitisOccurs in annual rainy season outbreaksOccurs in annual rainy season outbreaksResponsible for Responsible for fulminantfulminant hepatitis, hepatitis, especially in pregnant womenespecially in pregnant womenCauses sporadic and epidemic diseaseCauses sporadic and epidemic diseaseSurveillance in military = 2% AR/yr in Surveillance in military = 2% AR/yr in Kathmandu ValleyKathmandu Valley

Major health problem for soldiersMajor health problem for soldiers

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Study site & populationStudy site & population

SEX N MEANAGE

SD MIN MAX

F 8 29.6 10.07 20 47

M 1992 25.2 6.23 18 62

TOTAL 2000 25.2 6.25 18 62Shree Birendra

Hospital, Kathmandu

• Active duty Nepal Army members

• Male or female of age ≥18 years

• Consenting to participate

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Surveillance for diseaseSurveillance for disease

Military personnel were enrolled from 45 Nepalese Army Military personnel were enrolled from 45 Nepalese Army unitsunits

Active F/U every other week by a unit health workerActive F/U every other week by a unit health workerClinic and hospitalClinic and hospital--based surveillance dailybased surveillance daily

Suspected cases were evaluated with clinical labs (ALT, Suspected cases were evaluated with clinical labs (ALT, bilirubinbilirubin, with QC by research team), with QC by research team)

If acute hepatitis suspected, 4 serum specimens (D0, 7, 14, 28) If acute hepatitis suspected, 4 serum specimens (D0, 7, 14, 28) and 2 stool specimens (D0, 3) were collected and 2 stool specimens (D0, 3) were collected These were shipped biThese were shipped bi--weekly to Bangkok for serologic and RTweekly to Bangkok for serologic and RT--PCR testingPCR testing

All medically significant illness All medically significant illness → hospitalization→ hospitalizationThese events were reported as Serious Adverse EventsThese events were reported as Serious Adverse Events

66

Examples of hepatitis E in the studyExamples of hepatitis E in the study

77

HepHep

E Case (1)E Case (1) (Stool samples (Stool samples negneg

for HEV RNA)for HEV RNA)

Symptoms:A = jaundice, B = fatigue, C = anoreixaD = abdominal discomfort, E = RUQ abdominal pain, F = nausea

88

HepHep

E Case (2)E Case (2) (Serum and stool pos for HEV RNA)(Serum and stool pos for HEV RNA)

Symptoms:A = jaundice, B = fatigue, C = anoreixaF = nausea, G = vomiting

99

HepHep

E Case (3)E Case (3) (Later presentation, brief HEV RNA positivity, lower (Later presentation, brief HEV RNA positivity, lower

max ALT but intense jaundice)max ALT but intense jaundice)

Symptoms:A = jaundice, B = fatigue, C = anoreixaD = abdominal discomfort, E = RUQ abdominal pain. F = nausea

1010

HepHep

E Case (4)E Case (4) (Early presentation, late (Early presentation, late seroconversionseroconversion

to to IgM/IgIgM/Ig, ,

HEV RNA 1HEV RNA 1stst

pos marker)pos marker)

Symptoms:A = jaundice, B = fatigueD = abdominal discomfortE = RUQ abdominal pain

1111

HepHep

E Case (5)E Case (5) (Intense jaundice, longer convalescence)(Intense jaundice, longer convalescence)

Symptoms:A = jaundice, B = fatigue, C = anoreixaE = RUQ abdominal pain, F = nauseaG = vomiting

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HepHep

E Case (6)E Case (6) ((ViremiaViremia

persisting 2 weeks after resolution of persisting 2 weeks after resolution of

symptoms)symptoms)

Symptoms:A = jaundice, B = fatigue, C = anoreixaF = nausea

1313

Hepatitis E cases: Hepatitis E cases: Duration, biochemistriesDuration, biochemistries

Group N Mean SD Min Q1 Median Q3 Max

Placebo 78 32.53 14.56 8.00 23.00 29.00 39.00 82.00

Vaccine 9 30.33 8.41 18.00 26.00 30.00 39.00 42.00

Total 87 32.30 14.03 8.00 23.00 29.00 39.00 82.00

Parameters Placebo Vaccine TotalN 78 9 87Mean 1488 1799 1520SD 1134 1147 1133Minimum 156 490 156

Q1 688 1040 756Median 1246 1290 1248Q3 1868 2323 1995Maximum 4829 4214 4829Geo. mean 1085 1504 1122

Duration in days

Max ALT (U/L)Parameters Placebo Vaccine TotalN 78 9 87Mean 10.36 10.35 10.36SD 6.13 5.14 6.01Minimum 0.62 5.00 0.62Q1 6.22 7.56 6.61Median 8.98 8.00 8.95Q3 13.11 10.90 13.11Maximum 31.40 19.62 31.40Geo. mean 8.44 9.41 8.54

Max Bilirubin (mg/dL)

No fulminant hepatitis, no deaths

1414

Diagnoses of hepatotrophic disease in the Total vaccinated cohort Placebo Vaccine Totaln n n

Clinically-suspected hepatitis E 92 19 111Serologically-confirmed hepatitis A (HAV-IgM) 0 0 0Serologically-confirmed hepatitis B (HBc-IgM) 12 0 1Hepatitis B carrier (HBs-Ag positive but HBc-IgM negative) 2 3,4 0 2Serologically-detected hepatitis C (HCV-IgG) 1 5 0 1Serologically-detected leptospirosis (Lepto-MAT and Lepto-IgM) 6 3,5,6 2 7,8 8Serologically detected scrub typhus (IgM by PANBIO test & IgM or IgG w. blot) 3 9,10 1 11 4Virologically and serologically confirmed hepatitis E 78 9 87

2 One subject = Hepatitis E and acute hepatitis B3 One subject = Hepatitis E in a HBV carrier (also possible recent leptospirosis infection) 4 One subject = Hepatitis E in a HBV carrier5 One subject = Hepatitis E in an HCV-exposed subject (also possible recent leptospirosis infection)6 Four subjects = Hepatitis E in subjects with possible recent leptospirosis infection7 One subject = Hepatitis E in a subject with possible recent leptospirosis infection8 One subject = “not hepatitis E” (Possible recent leptospirosis infection)9 One subject = Hepatitis E in a subject with possible recent scrub typhus infection10 Two subjects = Hepatitis E in subjects with possible recent scrub typhus infection11 One subject = Hepatitis E in a subject with a possible recent scrub typhus infection

Most clinically-suspected acute viral hepatitis was hepatitis E; co- infections with other agents were uncommon

1515

““Not hepatitis E” casesNot hepatitis E” cases

N = 24N = 24None had definitive serum markers for :None had definitive serum markers for :

HAV, HBV, HCVHAV, HBV, HCVScrub typhus, leptospirosisScrub typhus, leptospirosis

Two cases had HEV infection confirmed by Two cases had HEV infection confirmed by viremiaviremia and and IgMIgM

Both not hepatitis (ALT, Both not hepatitis (ALT, bilirubinbilirubin ≠≠ case def.)case def.)

Hepatitis E case ascertainment was adequate. Results confirm that hepatitis E is the major cause of acute viral hepatitis among adults in Nepal

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Safety outcomesSafety outcomes

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Occurrence of Adverse EventsOccurrence of Adverse EventsSpontaneous report of any adverse eventSpontaneous report of any adverse event VaccineVaccine PlaceboPlaceboReactogenicity subset (N=200)Reactogenicity subset (N=200)

Grade 3 (prevents daily activities)Grade 3 (prevents daily activities)28.0%28.0%3.3%3.3%

27.0%27.0%3.0%3.0%

Total cohort minus Total cohort minus reactoreacto subset (N=1800)subset (N=1800) 25.2%25.2% 24.9%24.9%

Serious adverse events (excluding Serious adverse events (excluding hephep E)E) VaccineVaccine PlaceboPlaceboReactogenicity subset (N=200)Reactogenicity subset (N=200)

InfectionsInfections13.5%13.5%73/135 events73/135 events

13.7%13.7%73/137 events73/137 events

Hepatitis E was the most common medically significant illness in

the placebo group

The next most common illness overall was enteric fever (2.0% in vaccine group, 2.4% in placebo group

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Category Total

MEDICINECOMMUNICABLE 247 (61.3%)

297 (73.7%)NON COMMUNICABLE 50 (12.4%)

DEATH 7 (1.7%)

DERMATOLOGICAL 5 (1.2%)

PREGNANCY 2 (0.5%)

PSYCHIATRIC 3 (0.7%)

READMISSION 14 (3.5%)

SURGICAL 72 (17.9%)

UNDIAGNOSED 3 (0.7%)

Total 403 (100%)

Serious Adverse Events (SAE)

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Serious Adverse Event: HEV003

13

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Rainy season

Rainy season

Rainy season

2020

Communicable diseases among Serious Adverse EventsPrimary Diagnosis Total %

HEPATITIS 91 36.8

ENTERIC

INFECTION 80 32.4

RESPIRATORY TRACT INFECTION 22 8.9

VIRAL FEVER 18 7.3

DIARRHOEA 9 3.6

MALARIA 6 2.4

INFESTATION 4 1.6

MUMPS 3 1.2

URINARY TRACT INFECTION 3 1.2

HERPES ZOSTER 2 0.8

LEPTOSPIROSIS 2 0.8

OTITIS MEDIA 2 0.8

CONJUNCTIVITIS 1 0.4

JAPANESE ENCEPHALITIS 1 0.4

MEASLES 1 0.4

RHEUMATIC FEVER 1 0.4

SEXUALLY TRANSMITTED DISEASE 1 0.4

Total 247 100.0

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SummarySummary

In Nepal, hepatitis E is the major cause of acute liver disease In Nepal, hepatitis E is the major cause of acute liver disease in in adultsadultsActive surveillance found a 2Active surveillance found a 2--fold higher rate of hepatitis E than fold higher rate of hepatitis E than expectedexpectedAnnual disease intensity varies, so multiAnnual disease intensity varies, so multi--year evaluation of vaccine year evaluation of vaccine efficacy is usefulefficacy is usefulHepatitis E presents in varied ways Hepatitis E presents in varied ways

RTRT--PCR (serum) is the preferred diagnostic testPCR (serum) is the preferred diagnostic testSerology can be confirmatorySerology can be confirmatory

In this cohort, hepatitis E was the most common medically In this cohort, hepatitis E was the most common medically significant diagnosissignificant diagnosisSafety monitoring required evaluation of many other infectious Safety monitoring required evaluation of many other infectious illnessesillnessesGlobal attention is required for prevention of this disease in oGlobal attention is required for prevention of this disease in order to rder to reduce socio economic burden and maternalreduce socio economic burden and maternal--perinatalperinatal mortality in mortality in endemic region.endemic region.

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BibliographyBibliographyAshmaAshma RanaRana, , GeetaGeeta GurungGurung, et al. (AOCOG, et al. (AOCOG--2007), “2007), “AlrarmingAlrarming rise in rise in deaths from hepatitis in recent 5 years (2002deaths from hepatitis in recent 5 years (2002--2006): A changing pattern of 2006): A changing pattern of maternal mortality over the last decade” 06Cmaternal mortality over the last decade” 06C--5, 215, 21--25 Sep 2007, Tokyo, 25 Sep 2007, Tokyo, JapanJapan

Shrestha, M. P., R. M. Scott, et al. (2007). "Safety and efficacShrestha, M. P., R. M. Scott, et al. (2007). "Safety and efficacy of a y of a recombinant hepatitis E vaccine." recombinant hepatitis E vaccine." N N EnglEngl J MedJ Med 356(9): 895356(9): 895--903.903.

Shrestha, S. M. (2006). "Hepatitis E in Nepal." Shrestha, S. M. (2006). "Hepatitis E in Nepal." Kathmandu Kathmandu UnivUniv Med J Med J (KUMJ)(KUMJ) 4(4): 5304(4): 530--44.44.

Shrestha, K (2001). “Hepatitis E in the Royal Nepal Army and theShrestha, K (2001). “Hepatitis E in the Royal Nepal Army and theKathmandu valley.” MJSBH Platinum Jubilee 2057: 1Kathmandu valley.” MJSBH Platinum Jubilee 2057: 1--99

Final Clinical Study Report: “A phase II, prospective, RandomizeFinal Clinical Study Report: “A phase II, prospective, Randomized, Doubled, Double--blind, Placebo Controlled, Field Efficacy Trial of a candidate Hblind, Placebo Controlled, Field Efficacy Trial of a candidate Hepatitis E epatitis E Vaccine in Nepal”Vaccine in Nepal”

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AcknowledgementAcknowledgement

Julie A Pavlin, GEISJulie A Pavlin, GEIS--AFRIMSAFRIMSMammen P Mammen, USAMMDAMammen P Mammen, USAMMDARobert A Kushner, WRAIRRobert A Kushner, WRAIRBruce L Innis, GSKBruce L Innis, GSKSanjaya K Shrestha, WARUNSanjaya K Shrestha, WARUNBinobBinob Shrestha, WARUNShrestha, WARUN