Issues and Challanges in Rota Viral Vaccines in Preterm.pptx

This presentation discusses the Challenges and Issues in the implementation of RV Vaccines in Preterm babies in NICUs

1. ROTAVIRUS OUTBREAK IN NURSERY AND ITS PRVENTION Moderator: Dr Vivek Goswami Panelist: Dr Ashwani Sood Dr Vivek Saxena Dr Anupama Saggar

2. ROTAVIRUS G Serotypes referred by serotype numbers (e.g., G1, G2) . | P Genotypes are denoted in brackets (e.g., P[8], P[4]). VP7 - Designates G serotype of Strain ( G lycoprotein) VP4 - Designates P serotype of Strain ( P rotease-sensitive protein ) J Health Popul Nutr 2000 Jun;18(1):5-14, Gastroenterology. 2009 May; 136(6): 1939–1951. Double-shelled, naked, round particles, viruses are about 70 nm diameter, contain 11 segments of double-stranded RNA

3. Rotavirus is a double-stranded RNA virus of the family Reoviridae. The virus is composed of three concentric shells that enclose 11 gene segments. The outermost shell contains two important proteins: VP7, or G-protein, and VP4, or P-protein. VP7 and VP4 induce neutralizing antibodies that are believed to be involved in immune protection. From 1996 through 2005, five genotypes of rotavirus (G1P[8], G2P[4], G3P[8], G4P[8] and G9P[8]) accounted for 90% of strains isolated from children younger than age 5 years in the United States Of these, genotype G1P[8] accounted for more than 75% of strains. In the recent past, G12P[8] has become the most common genotype identified in the United States.

4. Why Focus on Neonatal Nurseries? Vulnerability of newborns. High risk of rapid spread in a confined environment.

5. Prevalence of Rotavirus Infection in Nurseries According to the age at NICU admission, the prevalence of rotavirus was 2.6% within 24 h of birth, 4.9% at 25–48 h, and 33.8% succeeding 48 h after of birth. The prevalence of rotavirus was significantly higher for NICU admissions admitted succeeding 48 h after birth than for within 48 h ( P  < 0.001). In a sub-analysis of 576 infants transferred succeeding 48 h after birth, there was no statistical difference between the two groups in GA, birth weight, and Apgar score. Higher prevalence among out-born newborns transferred to NICUs.

6. Rotavirus Infection Fever Watery Stools Vomiting + / Transmission of Rotaviral Infection Confirmation of Rotaviral Infection By Detection of Rotavirus Adapted from the WHO Rotaviral pamphlet

7. Risk Factors Hospitalization after 48 hours of birth. Use of postpartum care centers. The rotavirus positive group had a significantly higher gestational age, birth weight, and Apgar score. They also had a significantly higher rate of postpartum care centers when compared to the rotavirus negative group (45.5% vs. 12.6%,  P  < 0.001). Notably, the prevalence of rotavirus was significantly increased from 3.2 to 33.8% when infants were hospitalized 48 h after birth ( P  < 0.001).  yo jin kim et al

8. Case Studies : Notable Outbreaks Shim et al: 1 year prospective study in South Korea The prevalence of rotavirus infections was 25.2%. Preterm( rota +) differed from Preterm(- rotae ) and FT/NT( rota +) with respect to frequent feeding difficulty (p Z 0.047 and 0.034, respectively) and higher percentage of neutropenia (p Z 0.008 and 0.011, respectively). G4P[6] was the exclusive strain in both the Preterm( rotaþ ) (97.7%) and FT/NT( rotaþ ) (90.2%), and it was the same for nosocomial, institutional infections, and infections acquired at home.

9. Ramani et al: a 4-year prospective surveillance in the neonatal nurseries of a tertiary care hospital in south India : Rotavirus was detected in 43.9% neonates, including those with and without gastrointestinal disease. Rotavirus detection was significantly higher among neonates with GI disease (55.5%) than asymptomatic neonates (44.4%) (P 0.001). G10P11 was the most common genotype associated with both symptomatic and asymptomatic infections.

10. Clinical Manifestations

11. Clinical Manifestations Ranges from asymptomatic to severe gastroenteritis. Rotavirus was seen in association with diarrhea , vomiting, feed intolerance, necrotizing enterocolitis, hematochezia , gastroesophageal reflux, and abdominal distension. Potential complications like necrotizing enterocolitis, seizures and white matter injury

12. Infection Control Measures Hand hygiene. Rotavirus vaccine cannot be administered to neonates, so the prevention of infection in this group, by such methods as hand washing and cohort care, is particularly important. Rotavirus is non-envelope virus that cannot be inactivated by alcohol, so strict hand washing must be advocated. Surface disinfection. Isolation of infected infants. Vaccination

13. Types of Vaccines Rotarix® (RV1) : Given in 2 doses at 10, and 14 weeks of age. RotaTeq® (RV5) : Given in 3 doses at 6, 10, and 14 weeks of age. Rotavac ® : Given in 3 doses at 6, 10, and 14 weeks of age. Rotasiil ® : Given in 3 doses at 6, 10, and 14 weeks of age.

14. GENE Origin Of Rotavirus Vaccine Strains Due to minimal non-human origin DNA, high efficacy is expected in Developing countries. Bovine origin RV1 ROTAVAC RV5 RV5 (India) G1 P1A [8] G9 P[11] G1,G2,G3,G4,P1A[8] G1,G2,G3,G4,G9,P[5] 89-12 116-E 1 WC-3 VP 4 1 2 3 4 5 6 7 8 9 10 11 Gene Segments Human origin Human origin Bovine origin of genes 1 BK Das et al, Characterization of rotavirus strains from newborns in New Delhi, India., J Clin Microbiol ., 1994 Jul; 32(7): 1820–1822., 2 Das et al. Both Surface Proteins (VP4 and VP7) of an Asymptomatic Neonatal Rotavirus Strain (1321) Have High Levels of Sequence Identity with the Homologous Proteins of a Serotype 10 Bovine Rotavirus, Virology 194, 374-379, 1993,

15. Origins/ Source of Rotavirus Vaccines Vaccine RV Strains Receptors Dose Volume Storage Temperature Reconstitution Rotarix G1(Human) P[8] (Human) Le b 1 mL 2-8°C Required Rotateq No known human receptor Le b 2 mL 2-8°C G1 (Human) P[5] (Bovine) G2 (Human) P[5] (Bovine) G3 (Human) P[5] (Bovine) G4 (Human) P[5] (Bovine) G6 (Bovine) P[8] (Human) Not Required Rotasiil No known human receptor 2 / 2.5 mL 2-8°C G1 (Human) P[5] (Bovine) G2 (Human) P[5] (Bovine) G3 (Human) P[5] (Bovine) G4 (Human) P[5] (Bovine) G9 (Human) P[5] (Bovine) Required/Not Required ( based on vaccine form) 2-8°C G9(Human) P[11](Bovine) (116E Strain) Type 2 Precursor 5 drops/ 0.5 mL Not Required Type 2 Precursor -20°C G9( Human) P[11](Bovine) (116E Strain) 5 drops/0.5 mL Not Required to Infect regardless of Blood groups, unlike others 1 ROTAVAC vaccine’s viral Strain (116E) is naturally attenuated and reassorted. It’s P[11] allows it: infect even neonates, provides High efficacy in developing countries with just 0.5ml/ 5 drops per dose. 1 Emerging Microbes & Infections (2017) Apr 12;6(4): e22

16. Effectiveness RotaTeq® (RV5) : 98% effective against severe rotavirus gastroenteritis, 74% against any rotavirus gastroenteritis. But in developing countries the efficacy drops to 17-63%. Rotarix® (RV1) : 85-96% effective against severe rotavirus gastroenteritis, 87% against any rotavirus gastroenteritis. In developing countries the efficacy is 22-40% Rotavac ® : 56% effective against severe rotavirus gastroenteritis in the first year of life and 55% in the second year Rotasiil ® : 39.5% effective against severe rotavirus gastroenteritis in the first year of life.

17. Special Considerations Vaccination can be given to preterm infants if they are clinically stable and at least 6 weeks old. Contrindications : Severe allergic reaction to a vaccine component or following a prior dose of vaccine infants with a severe allergy to latex should not receive RV1 vaccine History of intussusception Severe combined immunodeficiency (SCID) Precautions: Moderate or severe acute illnesses, including gastroenteritis Not considered as precautions: Infants living in households with immunocompromised persons Infants living in households with pregnant women

18. Vaccine Strain - 116-E Replicates in infected newborns without causing disease Induces robust immune response even in presence of high titers of maternal antibody Due to binding to HBGA Type 2 precursor, may be ideal for birth dose. ROTAVAC ® vaccine strain isolated from asymptomatic neonates Naturally attenuated

19. THE LANCET Efficacy of a monovalent human-bovine(116E) rotavirus vaccine in Indian infants: a randomized, double-blind, placebo-controlled trial Conclusion 1 st year efficacy against severe Rotavirus Gastroenteritis= 56.3% Durable efficacy in the second year of life = 55.1 Phase 3 Efficacy Trial PROVEN LONG TERM EFFICACY RVGE Severity Vesikari score (>11) & very Severe (>16) Very Severe Severe Any Severity Vaccine Efficacy (%) 10 20 30 40 50 60 70 49.8 57.2 56.3 55.1 35 36.4 2 nd Year Of Age 1 st Year Of Age RVGE: Rotavirus Gastroenteritis; Bhandari N et al, India Rotavirus Vaccine Group. Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian infants: a randomised , double-blind, placebo-controlled trial. Lancet. 2014 Jun 21;383(9935):2136-43.

20. Cross Protection ROTAVAC ® demonstrates broad heterotypic cross- protection against major circulating strains Broad heterotypic cross- protection 1 RV Genotypes OTHERS which are protected against include G9P[8], G1P[4], G1P[6], G2P[6],G12P[11] OTHERS Vaccine Efficacy (%) 10 20 30 40 50 60 70 42 63.4 69.7 80 G12P [8] G12P [6] G2P[4] G1P[8] 69.2 67.1 1 . Nita Bhandari, et al., Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian infants:a randomised , double-blind, placebo-controlled trial. Lancet 2014 Jun 21; 383 (9935):2136-43.

21. White Paper Safety of Rotavirus Vaccine in India Self-controlled case series analysis demonstrated NO increased risk of intussusception associated with ROTAVAC ® vaccination in two separate analyses conducted by the Govt. of India. Rotasiil Rotavac ® White paper, Safety of Rotavirus vaccine in India (Smart Safety Surveillance {3S} Approach)

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