Rotavirus Infections and Vaccinations in

Rotavirus Infections and Vaccinations in Children under Five in Lebanon Hassan Zaraket, RPh, PhD Assistant Professor Department of Microbiology and Immunology Member, Center for Infectious Diseases Research American University of Beirut Disclosures: No conflicts of interest

Learning points 1 2 3 What is rotavirus disease? What are the signs and symptoms of rotavirus? How is rotavirus spread? 4 What are rotavirus prevention strategies? 5 What are the burden and prevalent rotavirus genotypes in Lebanon?

Rotavirus is the most common diarrheal pathogen Industrialized countries Less developed countries cases (%) Number of 100 Unknown 90 Bacteria Astrovirus 80 Calicivirus Adenovirus 70 Rotavirus 60 50 40 30 cases (%) Number of 100 90 80 70 60 50 40 30 Unknown Parasites Other bacteria Escherichia coli Adenovirus Calicivirus Adenovirus Rotavirus 20 20 10 10 0 0 1. Kapikian AZ and Chanock RM. In: Fields Virology 3 rd ed, Philadelphia, PA: Lippincott Raven. 1996:1657 708. 2. WHO. Wkly Epidemiol Rec 2008;83:421 5

Who is most at risk in the population? Infants after the age of 3 months Low to no immunity Vulnerable to dehydration Baby > 3 months Immuno- compromised children Older children if they are immunocompromised Risk of disea ase Adults Elderly Population

Estimated global prevalence of rotavirus disease Parashar et al, Emerg Inf Dis 2003 Global burden

Rotavirus prevalence in Lebanon 3 years surveillance in children <5 year of age 866 (61%) 548 (39%) 35% 30% 25% 20% 15% 10% 5% Percentage distribution of RV GE cases by age group (n= 548) 61 (11%) 110 (20%) 83% 107 (20%) 175 (32%) 58 (11%) 19 (3%) 18 (3%) RVGE Non RVGE 0% 0-4m 4-8m 8-12m 1-2yr 2-3yrs 3-4yrs 4-5yrs Source: Dr. Ghassan Dbaibo, AUBMC

Distribution of rotavirus gastroenteritis cases per hospital 60% 119 (56%) 50% 40% 30% 92 (44%) 32 (37%) 53 (34%) 191 (34%) 61 (32%) 20% 10% 0% Source: Dr. Ghassan Dbaibo, AUBMC Nabatieh Hammoud RHUH AUB NINI Makassed

Clinical features of rotavirus infection Day: 1 2 3 4 5 6 7 8 9 Incubation Symptomatic period 2 period 1 bd i l i 2 Diarrhea 3 Abdominal pain 2 Vomiting 3 Fever 39 C 3 Headache 2 Nausea 2 Malaise 2 1. Raebel MA and Ou BS. Pharmacotherapy 1999;19:1279 95. 2. Anderson EJ and Weber SG. Lancet Infect Dis 2004;4:91 9. 3. Staat MA, et al. Pediatr Infect Dis J 2002;21:221 7

Severe rotavirus gastroenteritis RVGE can be severe enough to require hospitalization ti in young infants and children 1 RV infection is unpredictable with symptoms that include: 2 Severe diarrhea Vomiting Fever Dehydration Electrolyte disturbances Shock 1. Flewett T, et al. J Clin Pathol 1976;27:608 14. 2. Staat M, et al. PAS 2009. May 2009. Baltimore, MD and pers comm

How does rotavirus spread? Rotavirus infection is highly hl contagious Fecal matter from infected infants contains as many as 10 12 particles per gram Rotavirus spread by fecal oral oralrouteroute The primary mode of transmission of rotavirus is the passage of the virus in stool to the mouth of another child 1. Hrdy. Rev Infect Dis 1987;9:461 9

Prevention of rotavirus gastroenteritis: Vaccination

The clinical basis for rotavirus vaccination Two natural infections provide 100% protection against subsequent moderate/severe disease Nearly 50% of children suffered a third infection, but all were either asymptomatic or were associated with only mild illnesses Probability of rotavirus in nfection 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 1st infection 2nd infection 3rd infection 4th infection 5th infection Moderate severe Mild asymptomatic Asymptomatic or mild illness 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Age (months) Adapted from Velázquez et al. N Engl J Med 1996;335:1022 8

Goal of rotavirus vaccination To mimic protection conferred by natural rotavirus infections Two natural rotavirus infections provide 100% protection against a subsequent moderate/severe infection Two vaccine infections could po provide ~50% protection potecto against infection and ~100% protection against moderate to severe disease rotavirus infe ection Probability of 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Two vaccine doses 1 st natural infection becomes the third encounter with a rotavirus 4th infection 5th infection Moderate severe Mild asymptomatic 1 2 3 4 5 6 7 8 9 101112131415161718192021222324 Age (months) Adapted from Velázquez et al. N Engl J Med 1996;335:1022 8

Rotavirus structure Virus particles possessa a triple layered layered icosahedral protein capsid composed ofan outer layer, an intermediate layer and an inner core layer 1 Outer capsid contains VP4 and VP7 antigens which induce neutralizing antibodies directed against rotavirus 1 Inner capsid contains VP6 antigen, the major RV group antigen (comprising >80% protein mass of particle) 2 Genome consists of 11 segments of double stranded RNA 1,2 MIDDLE CAPSID VP6 Groups (7) A, B, C, D, E, F, G Family: Reoviridae OUTER CAPSID VP7, VP4 G and P Types VP7 VP4 G P 1. Estes M, et al. In: Fields Virology (Knipe DM, et al., eds). 2001;1787 825. 2. Estes MK, et al. J Virol 1987;61:1488 94

Common rotavirus genotypes Common G and P combinations: G1, G3, and G4 with P1A[8] 1,2 G2 with P1B[4] 1,2 G9 with P[8] or P[6] 1 1. Santos N and Hoshino Y. Rev Med Virol 2005;15:29 56. 2. Gentsch JR, et al. J Infect Dis 1996;17(suppl 1):30 6

Prevalence of rotavirus genotypes in Lebanon 180 160 140 120 100 80 60 40 20 Source: Dr. Ghassan Dbaibo, AUBMC 164 (38.2%) 95 (22%) 79 (18.4%) 72 (17%) 7 (1.6%) 5 (1.2%) 2 (0.5%) 2 (0.5%) 1 (0.2%) 1 (0.2%) 1 (0.2%) 0 G1P8 G9P8 G4P8 G2P4 G12P6 G9P6 G9P4 G3P6 G3P9 G2P8 G1P6 4-5yrs 4 3 4 2 1 3-4yrs 4 5 1 4 1 2-3yrs 18 3 11 15 1 1 1 1-2yr 60 20 33 21 2 3 2 1 8-12m 30 24 8 17 2 1 4-8m 36 21 17 11 1 1 0-4m 12 19 5 2 1

Seasonal variation of RVGE cases by yy year 2011, 2012 and 2013 50 45 40 35 30 25 20 15 10 5 0 G9P6 G1P6 G3P6 G9P4 G3P9 G2P8 G9P6 G12P6 G9P8 G2P4 G4P8 G1P8 Jan Feb Mar Apr May June July Aug Sep Oct Nov Dec Jan Feb Mar Apr May June July Aug Sep Oct Nov Dec Jan Feb Mar Apr May June Source: Dr. Ghassan Dbaibo, AUBMC 2011 2012 2013

Rotavirus FDA approved vaccines Bovine human reassortant t(rv5) G1P7[5], G2P[5], G3P[5], G4P[5], [ G6P[8] [ ] (5 relevant antigens) Covers G1, G2, G3, and G4 Three oral doses (2, 4, and 6 mos) WHO. Weekly Epi Rep 2007; 32: 285 86

Rotavirus FDA approved vaccines Bovine human reassortant t(rv5) G1P7[5], G2P[5], G3P[5], G4P[5], [ G6P[8] [ ] (5 relevant antigens) Covers G1, G2, G3, and G4 Three oral doses (2,4, and 6 mos) Human attenuated (RV1) G1P[8] (2 relevant antigens) Covers G1 and non G1 types (G3, G4, and G9) Two oral doses (2 and 4 mos) WHO recommended in 2009 that they are included in national immunization programs WHO. Weekly Epi Rep 2007; 32: 285 86

Vaccines demonstrate high efficacy against RVGE Through h the first rotavirus season after vaccination: i RV1 1,2 RV5 2,3 96% efficacy against severe gastroenteritis 98% efficacy 87% efficacy against any severity of gastroenteritis 74% efficacy Up to 2 years after vaccination: in the combined incidence of hospitalizations/ed visits for gastroenteritis ~96% reduction ~96% reduction 1. Ruiz Palacios N Engl J Med 2006;354:11 22, 2. www.fda.org, 3. Vesikari T, Matson DO, Dennehy P, et al. N Engl J Med. 2006;354:23 33

Vaccines demonstrate high efficacy against RVGE Through h the first rotavirus season after vaccination: i RV1 1,2 RV5 2,3 96% efficacy against severe gastroenteritis 98% efficacy 87% efficacy against any severity of gastroenteritis Up to 2 years after vaccination: in the combined incidence of hospitalizations/ed visits for gastroenteritis 74% efficacy ~96% reduction ~96% reduction The most common adverse events: (occurred in vaccinated and placebo) RV1: fussiness, irritability, i cough, runny nose, fever, loss of appetite, vomiting, ii diarrhea RV5: diarrhea, vomiting, irritability, otitis media, nasopharyngitis, and bronchospasm 1. Ruiz Palacios N Engl J Med 2006;354:11 22, 2. www.fda.org, 3. Vesikari T, Matson DO, Dennehy P, et al. N Engl J Med. 2006;354:23 33

Rotavirus vaccine guidelines 2 (RV1) or 3 (RV5) oral doses beginning i at 2 months of age may be started as early as 6 weeks of age For both rotavirus vaccines maximum age for first dose is 14 weeks 6 days minimum interval between doses is 4 weeks maximum age for any dose is 8 months 0 days http://www.cdc.gov/vaccines/pubs/pinkbook/rota.html

Rotavirus vaccine guidelines 2 (RV1) or 3 (RV5) oral doses beginning at 2 months of age may be started as early as 6 weeks of age For both rotavirus vaccines maximum age for first dose is 14 weeks 6 days minimum interval between doses is 4 weeks maximum age for any dose is 8 months 0 days Rotavirus Vaccine Contraindications: Severe allergic reaction to a vaccine component (including latex) or following a prior dose of vaccine latex rubber is contained in the RV1 oral applicator History of intussusception Severe combined immunodeficiency (SCID) http://www.cdc.gov/vaccines/pubs/pinkbook/rota.html

Do these vaccines work?

Post licensure vaccine effectiveness and impact In the USA, RV5 used predominantly Equivalent reductions in ED visits and hospitalizations due to rotavirus were observed The National Respiratory and Enteric Viruses Surveillance System (NREVSS): http://www.cdc.gov/vaccines/pubs/surv manual/chpt13 rotavirus.html

How are we doing in Lebanon?

Rotavirus vaccination rate among all patients admitted with GE in Lebanon 1158 (82%) 27 (11%) 9 (3%) (RV1) Vaccine (RV5) Vaccine Unkown type 254 (17%) 219 (86%) Non Vaccinated Cohort% Vaccinated Cohort% 2 (1%) Unknown Vacc.% Source: Dr. Ghassan Dbaibo, AUBMC

Source: Dr. Ghassan Dbaibo, AUBMC Vaccination rates per center among patients admitted with GE

Rotavirus infections among vaccinated & non vaccinated patients The rate of RV in vaccinated (any dose) subjects= 50/254 (20%) The rate of RV in non vaccinated subjects= 379/1158 (33%) 475 (87%) 73 (13%) Vaccinated patients with Rota Positive GE Non Vaccinated patients with Rota Positive GE

Vaccinated Subjects One dose (RV1) Vac n= 54 (25%) n= 219 (86%) Two doses n=165 (75%) Vaccinated Subjects n= 254 (18%) (RV5) Vac n= 27 (11%) Unknown n= 9 (4%) One dose n=8 (30%) Two doses n=3 (11%) Three doses n=16 (59%)

Conclusions Rotavirus accounts for a significant burden of disease in hospitalized children under 5 years of age in Lebanon The majority of affected children are under 2 years of age Four major genotypes account for the majority of infected children Winter peak predominates Significant ifi breakthrough hinfection i in vaccinated children Rotavirus vaccines are highly effective

Acknowledgements American University of Beirut Medical Center (CIDR team) Hammoud Hospital (Dr. Ghassan Baasiri) Hotel Dieu de France (Dr. Bernard Gerbaka) Makassed General Hospital (Dr. Mariam Rajab) Nabatieh Hospital (Dr. Bassam Ghanem) Nini Hospital (Dr. Adlette Inati) Rafik Hariri University Hospital (Dr. Hassan Fakhoury) MSD for funding

Mutations in antigens of vaccine breakthrough g g strains

Vaccine Breakthrough The rate of RV in vaccinated (any dose) subjects= 50/254 (20%) The rate of RV in non-vaccinated subjects= 379/1158 (33%) (RV1) Vaccine breakthrough: 40/219 (18%) (RV5) Vaccine breakthrough: 7/27 (26%) Unknown vaccination breakthrough: 3 subjects

Breakthrough Rotavirus Gastroenteritis Among Vaccinated & Non-Vaccinated Patients By PCRs All PCRs 548 Positive PCR 429 Negative PCR 138 50 among vacc (11.6%)

(RV1) Vaccine Breakthrough 35% 30% 33% 30% 25% 20% 15% 10% 20% 15% 5% 0% 3% G2P[4] G1P[8] G9P[8] G4P[8] G2P[8] Percentage genotype distribution of (RV1) Vaccine breakthrough subjects (n= 40)

Genotypes among RV1 vaccine breakthrough [Total no: 40 ; 1 unknown date] 25% 20% 15% 10% 8 20% 4 10% 4 10% 9 23% 6 15% 7 18% 1st dose 2nd dose 5% 1 3% 1 3% 0% G1P[8] G2P[4] G2P[8] G4P[8] G9P[8] P t t di t ib ti frv1 i Percentage genotype distribution of RV1 vaccine breakthrough subjects per # of doses

Vaccine Breakthrough Ratio Among All Vaccinated Patients By PCR; Comparing The Two Vaccine Types 250 219 (100%) 200 150 100 50 0 40 (18%) (RV1) Vaccine Vaccinated Patients 27 (100%) 7 (26%) (RV5) Vaccine Vaccine Breakthrough

(RV5) Vaccine Breakthrough 50% 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% 43% 29% 14% 14% G4P[8] G1P[8] G2P[4] G9P[4] Percentage genotype distribution of (RV5) Vaccine breakthrough subjects (n= 7)

(RV5) Vaccine Breakthrough 35% 30% 25% 2 29% 2 29% 20% 1 1 1 1st dose 15% 14% 14% 14% 2nd dose 3rd dose 10% 5% 0% G1P[8] G2P[4] G4P[8] G9P[8] Percentage genotype distribution of (RV5) Vaccine breakthrough subjects per no. of doses

Reassorted Rotavirus Vaccine, RV5 Demonstrated Substantial Efficacy Against G1, G2, G3, org4 RVGE a in REST b Through the first rotavirus season after vaccination: 98% efficacy against severe RGE (N=5,673) 74% efficacy against any severity of RGE (N=5,673) Up to 2 years after vaccination: in the combined incidence of ~95% reduction hospitalizations/ed c visits for RGE (N=68,038) In clinical trials, the most common adverse events included diarrhea, vomiting, irritability, otitis media, nasopharyngitis, and bronchospasm. Vesikari T, Matson DO, Dennehy P, et al. N Engl J Med. 2006;354:23 33. a RVGE=rotavirus gastroenteritis; b REST=Rotavirus Efficacy and Safety Trial; c ED=emergency department.

In the USA, RV5 used predominantly: Diarrhea-Associated Health Care Utilization among Children under 5 Years of Age According to Month and Setting, January 2001 June 2009. Hospitalization Emergency Department Visit Outpatient Visit Cortes JE et al. N Engl J Med 2011;365:1108-1117

Diarrhoea and rotavirus related admissions among children aged less than 5 years at seven hospitals in El Salvadorde Palma, et al 2010

Type of Rotavirus vaccine received 27 (11%) 9 (3%) (RV1) Vaccine (RV5)V Vaccine Unkown type 219 (86%)

Vaccination Rates per Center Among Patients Admitted with GE 70% 60% 50% 40% 30% 20% 10% 0% 3 (60%) 61 (39%) 57 (27%) 52 (25%) 59 18 (11%) (10%) 4 (5%) HD AUB Hammoud NGUH Nini Makassed RHUH