Established and new rotavirus vaccines: a comprehensive review for healthcare professionals

Figures & data

Figure 1. Rotavirus structure and potential vaccine targets.

RNA, ribonucleic acid; VP, structural protein.

Table 1. Characteristics of rotavirus single-strain vaccines based on neonatal or live-attenuated human RV strains

	HRV (Rotarix)	Rotavin-M1	116E (Rotavac)*	RV3-BB (in development)
Basic concept (composition/strain)	Human, live-attenuated G1P [8] RV vaccine.^Citation19	Human, live-attenuated G1P[8] RV vaccine.^Citation30	Live-attenuated, naturally reassorted human-bovine single strain G9P[11] vaccine, containing one bovine RV gene P[11] and 10 human RV genes including G9.^29,Citation31	Human, neonatal G3P[6] RV vaccine.^Citation32
Manufacturer, country, licensure and WHO prequalification	GSK; first approved in Mexico in 2004, Europe in 2006 and USA in 2008(WHO-prequalified vaccine).^Citation19	Center for Research and Production of Vaccines and Biologicals (Polyvac); national license granted by Vietnam in 2012.^Citation30,Citation33	Bharat Biotech Int. Ltd and Department of Biotechnology, Government of India; licensed in India in 2014. (WHO-prequalified vaccine).^Citation34,Citation35	Murdoch Children’s Research Institute/Biofarma; phase III development in Australia, New Zealand and Indonesia.^Citation32
Dosage and schedule, presentation, and shelf life	2 oral doses: first dose administered from age 6 weeks. At least 4 weeks between doses. Course must be preferably completed by 16 weeks and always before 24 weeks of age.^Citation19 Liquid: either oral applicator or oral tube; shelf life of 3 years at 2–8°C.Lyophilized: oral applicator; shelf life of 3 years at 2–8°C.^Citation19	2 oral doses administered 2 months apart. The first dose must be administered at 6–12 weeks of age.^Citation33 Liquid; 24 months at −20°C 2 months from thawing at 5°C.^Citation33	3 doses at 6, 10, and 14 weeks of age. Oral liquid, frozen; shelf life of 5 years at −20°C or 6 months at 5 ± 3°C. Fully liquid also available.^Citation31	3 oral doses administered as either a neonatal schedule (0–5 days, 8 weeks, and 15 weeks of age) or an infant schedule (8, 15, and 24 weeks of age). Liquid; n published data on storage conditions.^Citation32
Protection against non-vaccine strains	Broad protection demonstrated.^Citation19	No published results.	Efficacy against heterotypic G1P[8], G2P[4], G12P[6], and G12P[8] RV strains and partially heterotypic G9P[4] strain demonstrated in a phase III trial.^Citation29,Citation31	No published results.
Vaccine efficacy, %; and/or immunogenicity,%	Low-income African and Asian countries: 61.2%–100% (severe EP)^Citation19 High-income and upper-middle-income countries: 95.8% (severe EP)^Citation19 LATAM countries: Efficacy against RVGE-associated hospitalizations/emergency visits: 83%–85%.^Citation19,Citation36	Vaccine immunogenicity (as RV IgA) seroconversion):^Citation30Higher titer (10^6.Citation3), 2-dose regimen: 73%Lower titer (10^6.0), 2-dose regimen: 61%.	Efficacy against severe RVGE (score ≥11/20):^Citation29,Citation31 In the first year of life: 56% [95% CI: 37–70]. In the second year of life: 49% [95% CI: 17–68].	Cumulative vaccine take after 3 doses:^Citation32Neonatal schedule: 90%Infant schedule: 93%. Vaccine efficacy against severe RVGE in Indonesia:^Citation37 Neonatal schedule: 75% [95% CI: 44–91]Infant schedule: 51% [95% CI: 7–76]
Vaccine effectiveness, %	Effectiveness against combined RV hospitalizations, emergency visits, and outpatient visits:^Citation38,Citation39High-income (low child mortality) countries: 81%–84%Upper-middle-income (medium child mortality) countries: 54%–75%Lower-middle-income (high child mortality) countries: 63% – 57%	No published results.	No published results.	No published results.
Safety	Well characterized safety profile Large post-marketing studies Benefit-risk ratio positive Continuous safety monitoring^Citation20	Acceptable safety profile in one clinical trial (with limited sample size).^Citation30	Acceptable safety profile in a few clinical trials (with limited sample size). Recent implementation of nationwide safety surveillance^Citation40	Acceptable safety profile in a few clinical trials (with limited sample size).^Citation32

*Naturally occurring human-bovine reassortant; CI, confidence interval; EP, endpoint; IgA, immunoglobulin A; LATAM, Latin America; RV, rotavirus; RVGE, rotavirus gastroenteritis.

Table 2. Characteristics of rotavirus single-strain vaccines based on live-attenuated animal RV strains

	LLR (Lanzhou lamb rotavirus vaccine)
Basic concept (composition/strain)	Lamb, live-attenuated G10P[15] RV vaccine^Citation41
Manufacturer, country, licensure and WHO prequalification	Lanzhou Institute of Biomedical Products(China National Biotec Group [CNBG]).National license granted by China in 2000.^Citation41
Dosage and schedule, presentation, and shelf life	3 oral doses: 1 dose per year for 3 consecutive years in children aged 2–36 months. Liquid; shelf life of 1 year at 2–8°C.^Citation33,Citation42
Protection against non-vaccine strains	No published results.
Vaccine efficacy, %	No published results.
Vaccine effectiveness, %	1 dose of LLR compared with no vaccination:^Citation41,Citation43Effectiveness among children <5 years of age: 35% [95% CI: 13–52]; 52% against G3 [95% CI: 2–76].^Citation44Effectiveness among children <24 months of age: 77% [95% CI: 64–86].^Citation43
Safety	No published data in English language.

RV, rotavirus; RVGE, rotavirus gastroenteritis; CI, confidence interval.

Table 3. Characteristics of rotavirus multi-strain vaccines based on live-attenuated bovine-human reassortant RV strains

	HBRV (RotaTeq)	BRV-PV (Rotasiil)	Tetravalent UK-BRV	Hexavalent UK-BRV	Pentavalent UK-BRV
Basic concept (composition/strain)	Live-attenuated, human-bovine reassortant vaccine: 5 reassortant strains in one vaccine containing human G1, G2, G3, G4 (VP7) and P[8] (VP4) inserted into the bovine G6P[5].^Citation20	Live-attenuated, human-bovine reassortant vaccine: 5 reassortant strains in one vaccine containing human G1, G2, G3, G4 and G9 (VP7) inserted into the bovine G6P[5] UK strain.^Citation45,Citation46	Live-attenuated, human-bovine reassortant vaccine: 4 reassortant strains including human G1–4 inserted into the bovine G6P[5] UK strain.	Live-attenuated, human-bovine reassortant vaccine: 6 reassortant strains including human G1–4, G8, G9 inserted into the bovine G6P[5] UK strain.^Citation47	Live-attenuated, human-bovine reassortant vaccine: 5 reassortant strains including human G1–4, G9 inserted into the bovine G6P[5] UK strain
Manufacturer, country, licensure and WHO prequalification	Merck & Co, Inc (MSD); licensed by FDA and EMA in 2006(WHO-prequalified vaccine).	Serum Institute of India Limited; licensed in India in 2017. (WHO-prequalified vaccine).	Developer: Shantha Biotechnics (phase I/II development) – development abandoned.	Developer: Wuhan Institute of Biological Products, China. Development phase: phase I, age-descending study completed in China (ChiCTR-PIR-16,008,824).^Citation47	Developer: Instituto Butantan, Brazil. Development phase: phase I study in Brazil.^Citation48
Dosage and schedule, presentation, and shelf life	3 doses administered ≥4 weeks apart; the 3-dose course should be completed by 20–22 weeks of age and not later than 32 weeks of age. The first dose is administered between 6–12 weeks of age. Oral, liquid, squeezable tube;shelf life of 2 years at 2–8°C.	3 doses at 6, 10, and 14 weeks of age.^Citation49 Oral, lyophilized product to be reconstituted before administration; shelf life of 36 months below 25°C, 18 months between 37°C and 40°C and short time periods over 55°C.^Citation50	3 doses: initial dose at 6–8 weeks and following doses at 4-week intervals.Oral, liquid, ready to administer.	No information available.	No information available.
Protection against non-vaccine strains	Broad protection largely demonstrated.^Citation20,Citation28	No published results.	No published results.	No published results (early phase clinical development).	No published results (early phase clinical development).
Vaccine efficacy, % [95% CI] and/or immunogenicity,%	Low-income African and Asian countries:^Citation51–53 34%–87.5%.High-income and upper-middle-income countries:^Citation21,Citation22,Citation54,Citation55 85%–98%.LATAM countries:^Citation36Efficacy against RVGE-associated hospitalizations/emergency visits: 90%.	Efficacy against RVGE in Niger:^Citation45Severe cases (per-protocol analysis): 67% [50–78]. Efficacy against RVGE in India:^Citation49Severe cases (per-protocol analysis): 36% [12–54]Very severe cases: 61% [18–81]. Anti-RV IgA seroconversion after 3 doses:^Citation46 60%.	A phase I/II study conducted in India showed seroresponse rates up to 83.3% depending on the viral titer.^Citation56 Non-inferiority over HBRV non demonstrated.^Citation57	No information available.	A phase I study in Brazil showed good safety profile and evidence of immunogenicity in adults.^Citation48
Vaccine effectiveness, % [95% CI]	Effectiveness against combined RV hospitalizations, emergency visits, and outpatient visits.^Citation39High-income (low child mortality) countries: 90%Lower-middle-income (high child mortality) countries: 45%	No published results.	No information available.	No information available.	No information available.
Safety	Well characterized safety profile. Large post-marketing studies. Benefit/risk ratio largely positive. Continuous safety monitoring.^Citation58	Acceptable safety profile in a few clinical trials (with limited sample size).	Acceptable safety profile in one clinical trial (with limited sample size).	No published results (early phase clinical development).	Acceptable safety profile in one clinical trial (with limited sample size).

BRV-TV G1–4 tetravalent candidate (Shantha Biotechnics, India); CI, confidence interval; EMA, European Medicines Agency; FDA Food and Drug Administration; G1–4, 8, 9-hexavalent candidate, human-bovine reassortant hexavalent RV vaccine (Wuhan Institute of Biological Products, China); G1–4, 9-pentavalent candidate, human-bovine reassortant pentavalent RV vaccine (Instituto Butantan, Brazil); IgA, immunoglobulin A; LATAM, Latin America; RV, rotavirus; RVGE, rotavirus gastroenteritis.

Table 4. Characteristics of new rotavirus vaccines in early phase development

	G1P[8], inactivated	P2-VP8-P[8] and P2-VP8-P[4/6/8]	MBP::VP6and pCWA:VP6	VP2/6/7andVP2/4/6/7VLPs	VP6 GI.3/GII.4 RV-NoV VLPs
Basic concept	Inactivated human RV vaccine.	Subunit RV vaccines based on recombinant proteins.		Subunit RV vaccines based on virus-like particles.
Composition	Thermally inactivated G1P[8] strain derived from a fecal specimen of a child in USA.	Monovalent P2-VP8-P[8]: 1 truncated human VP8 protein (P[8]) and the P2 epitope of the tetanus toxin. TrivalentP2-VP8-P[4/6/8]: 3 truncated human VP8 proteins (P[4], P[6], P[8]) and the P2 epitope of the tetanus toxin.	Recombinant murine VP6 protein expressed as chimera with MBP, and VP6-CWA protein expressed on the surface of L. lactis.	RV-VLPs: co-expression of VP2, VP6, VP4 and/or VP7 (expression systems using baculovirus, E.coli, plant or yeast).	Recombinant human RV VP6 protein combined with NoV VLPs.
Development phase and developer	Preclinical development.^Citation59,Citation60Centers for Disease Control and Prevention (CDC), USA.	Clinical development.^Citation61,Citation62 PATH Rotavirus Vaccine Program, USA.	Preclinical development.Cincinnati Children’s Hospital, USA; Laboratoria de Immunologia y Virologia (LIV), Argentina.	Preclinical development.Baylor College of Medicine, USA.	Preclinical development.University of Tampere School of Medicine, Finland.
Route of administration tested	Parenteral.	Parenteral.	Parenteral.	Parenteral.	Parenteral.
Results obtained	Three doses induced high titers of RV-specific IgG antibodies and heterotypic immunity in gnotobiotic piglets and guinea pigs.^Citation59,Citation60Mucosal immunity in the gut and strong serum immune response shown in mice.^Citation63,Citation64	Monovalent P2-VP8-P[8]: It was well tolerated and evoked immune responses when intramuscularly injected in healthy adults in USA^Citation61 and in South African toddlers and infants.^Citation62 Trivalent P2-VP8-P[4/6/8]: phase I/II trial completed in South Africa (NCT02646891) but results not available.	Intranasal administration of MBP::VP6 (together with an adjuvant) to mice conferred 98% protection against infection by a murine RV strain.^Citation65Humoral response of mice immunized with recombinant VP6 protein expressed on L. lactis proved to be immunogenic.^Citation66,Citation67	RV VLPs induced significant immune response independent of the immune route (intramuscular, intrarectal, intranasal, intraperitoneal or oral) in mice.^Citation68,Citation69	When delivered intranasally or intramuscularly to mice, this candidate vaccine was immunogenic and conferred protection against infection by a murine RV^Citation70–72
Additional information	Potential lower risk of IS. No risk of vaccine-derived reassortant strains. Inactivated vaccines are generally less efficacious than live vaccines.	Potential lower risk of IS. Non-oral RV vaccines could present higher efficacy in developing countries compared to oral RV vaccines. No risk of vaccine-derived reassortant strains. Potential protection against NoV and RV gastroenteritisin a single vaccine (for RV-NoV VLPs).VLPs are generally more immunogenic than subunit or recombinant immunogens.^Citation68Possible combination of an oral attenuated HRV vaccine with RV VLPs (avoiding the need of sequential doses with live vaccine).^Citation73

G1P[8], inactivated human RV vaccine (Centers for Disease Control and Prevention, USA); P2-VP8-P[8], monovalent subunit vaccine P2-VP8-P[8] (PATH Rotavirus Vaccine Program, USA); P2-VP8-P[4/6/8], trivalent subunit vaccine P2-VP8-P[4]P[6]P[8] (PATH Rotavirus Vaccine Program, USA); MBP::VP6, maltose-binding protein-VP6 protein chimera (Cincinnati Children’s Hospital, USA); VP2/6/7 VLPs (trivalent) and VP2/4/6/7 VLPs (quadrivalent), virus-like particles RV vaccine (Baylor College of Medicine, USA); VP6-GI.3/GII.4 RV-NoV VLPs, rotavirus-norovirus virus-like particles combination vaccine (University of Tampere School of Medicine, Finland).CWA, cell wall anchor; IgG, immunoglobulin G; IS, intussusception; MBP, maltose-binding protein; NoV, norovirus; RV, rotavirus; USA, United States of America; VLPs, virus-like particles PATH, Program for Appropriate Technology in Health.

Figure 2. Overview of the rotavirus vaccines included in this review reflecting their vaccine concept and type of strain.

RV, rotavirus; NoV, norovirus; Ov, ovine RV; Bov, bovine RV; Hu, human RV; Rh, rhesus RV; Hu-Bov, human-bovine reassortant RV; Hu-Rh, human-rhesus reassortant RV; VLPs, virus-like particles.* Vaccines derived from the bovine G6P[5] UK-BRV strain.† Human strain with a single gene segment encoding VP4 derived from a bovine rotavirus (natural bovine-human reassortant)Live vaccines (clockwise): HRV (Rotarix, GSK, Belgium); LLR (Lanzhou lamb RV vaccine, Lanzhou Institute of Biomedical Products, China); RV3-BB (human neonatal RV vaccine, Bio Farma Indonesia, Indonesia, and Murdoch Children’s Research Institute of Australia, Australia); 116E (Rotavac, Bharat Biotech, India); Rotavin-M1 (Polyvac, Vietnam); HRRV, human-rhesus reassortant RV vaccine (Wyeth, USA); HBRV (RotaTeq, Merck & Co., Inc, USA); BRV-PV (Rotasiil, Serum Institute of India, India); tetravalent UK-BRV (Shantha Biotechnics, India); hexavalent UK-BRV (Wuhan Institute of Biological Products, China); pentavalent UK-BRV (Instituto Butantan, Brazil).Inactivated vaccine: G1P[8], human inactivated RV vaccine (Centers for Disease Control and Prevention, USA).Subunit vaccines based on virus-like particles (VLPs): VP6-GI.3/GII.4, trivalent, RV-NoV virus-like particles combination vaccine (University of Tampere School of Medicine, Finland). VP2/4/6/7 RV quadrivalent, virus-like particles RV vaccine (Baylor College of Medicine, USA); VP2/6/7, trivalent, virus-like particles RV vaccine (Baylor College of Medicine, USA).Subunit vaccines based on recombinant proteins: MBP::VP6 and pCWA:VP6, maltose-binding protein-VP6 protein chimera and VP6-CWA fusion protein (Cincinnati Children’s Hospital, USA; Laboratorio de Immunologia y Virologia (LIV), Argentina); P2-VP8-P[8], monovalent P2-VP8 RV vaccine (PATH Rotavirus Vaccine Program, USA); P2-VP8-P[4/6/8], trivalent P2-VP8 RV vaccine (PATH Rotavirus Vaccine Program, USA).

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