Rotavirus vaccine development

Rotavirus vaccine development was initiated relatively soon after the discovery of the virus due to the early recognition of the burden of disease and mortality in infants and young children universally. Within 10 years, rotavirus vaccine trials were being prepared utilizing a live attenuated oral vaccine approach based on several observations, including (i) that primary natural infection led to protection against severe disease upon re-infection [26, 70], (ii) the antigenic relatedness of animal and human rotaviruses [34, 71], and (iii) early animal studies that indicated that protection against rota-virus disease was mediated primarily by intestinal immunity [72].

Table 2. Live oral rotavirus vaccine candidates which are currently licensed or in clinical development

Vaccine strain Type of vaccine

Company/ developer

Status

Inventor

Licensed vaccines

RotaShield®

RotaTeq®

Rotarix®

Quadrivalent reassortant rhesus rotavirus strain with human rotavirus VP7 genes for G1-G4

Monovalent lamb rotavirus

Pentavalent reassortant bovine strain with human rotavirus VP7 and VP4 genes to G1-G4 and P[8]

Monovalent human rotavirus strain G1P[8]

Wyeth Ayerst (USA)

Lanzhou Institute (China)

GlaxoSmith

Kline

(Belgium)

Licensed in USA (1998)

Licensed in China (2000)

Licensed in USA (2006)

Licensed in Mexico and in Europe (2006)

AZ Kapikian, NIH

ZS Bai, Lanzhou Institute

HF Clark, Wistar Institute

R Ward, Gamble Institute

Clinical development

116E and I321

Multivalent reassortant bovine strain with human rotavirus genes

Monovalent human neonatal rotavirus strain

Monovalent human-bovine reassortant strains

NIH with vaccine producers in Brazil, China and India

University of

Melbourne with

BioFarma, Indonesia

Indian/USA consortium

Phase 2 data available

Phase 2 data available. High titer strains

Phase 1 data available

AZ Kapikian, NIH

RF Bishop, University of Melbourne

MK Bhan, RI Glass, HB Greenberg, CD Rao et al.

Adapted from [6]

Although there are several licensed rotavirus vaccines and several under development (Tab. 2), the discussion in this review focuses on the two vaccines that have been developed by the multinational pharmaceutical industry and which are closest to be able to impact the global mortality due to rotavirus infection. These two vaccines have been evaluated for efficacy and safety in large clinical trials [14, 15], and licensed internationally by the FDA and/or the European Agency (EMEA).

Reassortant rotavirus vaccines using animal rotavirus strains

The protection observed by the primary rotavirus infection and the antigen-ic relatedness of animal and human rotaviruses, stimulated the "Jennerian" approach to rotavirus vaccination, which relied on immunization with animal rotavirus or animal-human reassortant rotavirus strains [56, 73]. Thus, attenuated animal rotavirus strains produced the first rotavirus vaccine candidates (Tab. 2) and continue to be a major source of the rotavirus vaccine development currently. The early rotavirus vaccine candidates included bovine strains (RIT4237 and WC3) and the monovalent parent rhesus rotavirus (MMU18006). After variable results with the monovalent rhesus G3 strain [74-76] and with the monovalent bovine strains, which carried a G6 serotype specificity that is not found in human strains [77-79], the approach shifted to developing reassortant vaccine strains [56, 59].

The concept of the Jennerian approach - that animal rotaviruses were attenuated for human disease - was modified to generate reassortant vaccine strains carrying the VP7 gene of one of the four most common human rotavirus VP7 strains (G1-G4) on the genetic background of the animal rotavirus strains. These reassortant vaccine candidates were developed to yield multiple strains that would offer a multivalent serotype exposure upon immunization, but which kept the attenuated nature of the parent strain [56, 59]. This approach yielded the tetravalent reassortant rhesus rotavirus vaccine candidate, which was licensed as RotaShield®.

Rhesus-human reassortant rotavirus vaccine

The quadrivalent rhesus-human reassortant rotavirus vaccine is based on the rhesus rotavirus (RRV) strain, which shares G3 specificity with human rotaviruses. Three reassortant rhesus strains with the VP7 gene from human rotaviruses for G1 (human strain D), G2 (strain DS-1) and G4 (strain ST3), respectively, were created [80]. The vaccine candidate consists of a pool of these reassortant strains with the parent strain RRV, but early studies showed each reassortant strain to be similar to the parent RRV strain in infants with regard to safety, reactogenicity, shedding and immunogenicity [56]. These studies also showed that protective efficacy was associated with the serological response as measured by the serum IgA response [56, 81].

A series of efficacy trials were conducted in different populations and at different vaccine concentrations (104 pfu and 105 pfu per dose) and in general showed consistent protective efficacy against all rotavirus diarrhea (50-60%) and against severe rotavirus disease (70-100%) (reviewed in [56]). The pivotal phase III efficacy trials, using three doses of the vaccine at 4 x 105 pfu per dose, showed protection against any rotavirus diarrhea of between 50-60% and against severe rotavirus diarrhea requiring hospi-talizations or rehydration of 70-100% [82-84]. The protective efficacy was exhibited against different circulating VP7 serotypes and was evident over two to three rotavirus seasons.

On the basis of these results, RotaShield®, was licensed in the United States by Wyeth Ayerst in 1998 and quickly implemented into the routine immunization schedule for USA infants [85]. However, within 9 months and after over half a million US infants had received the vaccine, there was a reported association of the vaccine with intussusception [86]. Although RotaShield® was licensed in the USA, the vaccine is no longer produced and has not been evaluated in clinical trials in children in developing countries. Questions remain whether the vaccine should have finished clinical evaluation in the developing world due to the high risk-benefit of a rotavi-rus vaccine where mortality is high due to rotavirus disease [87, 88].

The debate about the actual risk of the RotaShield® vaccine with intussusception continues [88, 89]; however, the vaccine was withdrawn by the manufacturer in October 1999, and the recommendation for its use was withdrawn by the Advisory Committee for Immunization Practices (ACIP). It remains unavailable today. The major safety concern currently is whether the new rotavirus vaccines will have the same association with intussusception, and it is likely that this can only be addressed in large post-marketing surveillance studies once the vaccines are introduced. This has been specifically requested by the WHO and will be specifically pertinent to all future rotavirus vaccines [90].

Reassortant WC3 bovine-human rotavirus vaccine

WC3 is a bovine rotavirus, bearing a G6P7[5] serotype, which is not found among human rotaviruses. The vaccine development is well described in earlier reviews [59, 69] and shows the safety and immunogenicity of the quadrivalent vaccine candidate [91, 92] and the final pentavalent reassortant vaccine with the reassortant strains containing the G1-G4 and P1A[8] human rotavirus genes [68, 69].

The parent strain, WC3, was consistently found to be safe and immunogenic in early studies, with neutralizing antibody responses in 71-97%, although the immune response was specific to bovine rotavirus [59, 93]. Various reassortant combinations with human rotavirus genes for serotypes G1-G4 and/or P1A[8] on the bovine WC3 background have been generated [59, 68]. A series of clinical trials utilizing the monovalent WC3 reassortant strains with human rotavirus G1 or G2 specificity illustrated the safety and immunogenicity of the vaccine components, and also illustrated that the immune response to the bovine rotavirus VP4 was significant and should be included in future vaccine candidates [94].

The pentavalent WC3 reassortant rotavirus vaccine candidate, which consists of reassortant strains with each of the human rotavirus genes G1-G4 and P[8], was recently licensed as RotaTeq® by Merck & Co., Inc., based a series of clinical trials that are described elsewhere [68, 69]. The pivotal safety and efficacy study was also recently reported [15]. The vaccine showed 74% protection against any rotavirus-associated diarrhea and 98% efficacy against severe rotavirus disease and was protective against all four human rotavirus strains (G1-G4) included in the vaccine and G9 strains which are not in the vaccine, but which share the VP4 P[8] genotype [15].

This study was also designed to examine any potential risk of association with intussusception and so enrolled over 70 000 infants in 11 countries in the US, Europe and Latin America. The infants were 6-12 weeks of age and received three doses of either the pentavalent vaccine or placebo in a blinded, randomized fashion. Active surveillance for cases of intussusception was conducted with adjudication by an independent safety monitoring board. Overall, 27 cases of intussusception were identified during a full year's follow-up of each subject, although these were evenly distributed between vaccine (12) and placebo groups (15). Only two cases were identified in the 14-day window after any dose and these were evenly split [15, 68].

Thus, this vaccine is licensed in the USA and has been recommend for use in universal immunization of American infants by the ACIP.

Monovalent lamb rotavirus (LLR)

A monovalent lamb rotavirus strain (G10P[12]) was isolated in primary calf kidney cells in China in 1985 and has been developed as a vaccine after multiple passaging [19]. The vaccine strain was developed at the Lanzhou Institute for Biological Products, and has been evaluated in clinical trials in China, showing a serum neutralizing response in 61% of vaccinees [19]. The trials were conducted in slightly older children and the immune responses resemble a "booster" response in these children, as it exhibits a similar elevation in titer of neutralizing antibody to all G1-G4 strains. This vaccine was licensed for use in China in 2000 and has been utilized in the private market since then [Zhi Sheng Bai (inventor), personal communication].

Reassortant UK bovine-human vaccine

A second bovine-human reassortant vaccine is based on the bovine strain UK (also G6P7), and contains the human rotavirus genes for serotype G1-G4 and P1A[8] reassorted onto the bovine rotavirus UK background [95]. The individual components of the vaccine were shown to be safe and immu-nogenic following two doses, as indicated by the presence of serum IgA [96]. Subsequently, the quadrivalent VP7-specific vaccine was administered in three doses at 105 plaque-forming units (pfu) to infants with concomitant childhood immunizations [97]. There was no adverse reaction with the other concomitant vaccines and 95% of the infants developed neutralizing antibody responses to the vaccine strain.

Several vaccine producers in Brazil, China and India are intending to license-in the UK vaccine strains and produce them locally on site. A full clinical development program will be required and efficacy trials with the vaccine candidate are planned in developing countries where the vaccines are to be produced. Although this development will take a number of years, the eventual capacity to produce supplies of vaccine and the likely prices of these vaccines should benefit the global market for rotavirus vaccines and particularly their introduction into other developing countries.

Monovalent human rotavirus vaccine strains

The concept of a monovalent human vaccine strain is predicated on the premises that (i) natural infection confers protection against subsequent disease [22, 26, 30, 31], and (ii) that neutralizing antibody is not the only immune effector of protection and that other immune factors do play a role in clinical protection [67].

Attenuated human rotavirus strain (89-12)

A naturally circulating human rotavirus strain associated with diarrheal disease was identified to confer natural immunity to subsequent rotavirus infection in infants and young children [58]. The strain (89-12), which was recovered from the stools of a 15-month-old toddler with rotavirus diarrhea, was shown to be protective against rotavirus disease in the following season. [58]. The rotavirus strain is G1P1A[8], which is the most predominant human rotavirus strain circulating globally and constitutes about 55% of all human rotaviruses [38]. The strain 89-12 was adapted to tissue culture and serially passaged to attenuate the strain as a vaccine candidate [98]. A clinical trial of the attenuated 89-12 vaccine strain was seen to offer 89% protective efficacy against any rotavirus disease and 100% against severe rotavirus infection in the subsequent season [99], and this protection was shown to extend over at least 2 years [100]. Initial trials demonstrated that the vaccine strain was safe and immunogenic and that after two doses, nearly every child (94%) developed an immune response.

The parent strain has been further developed by GlaxoSmithKline Biologicals who further attenuated the strain by passage in tissue culture, before cloning and purifying the end product (now designated strain RIX4414) [101]. This vaccine strain has been evaluated in several immu-nogenicity and efficacy studies globally including in Finland [102], Latin America [103] and Singapore [104]. The vaccine was first licensed in Mexico in 2004, based on clinical efficacy data generated in a phase III efficacy trial in Brazil, Mexico and Venezuela, where 1986 infants were vaccinated at 2 and 4 months with different vaccine concentrations at approximately 104, 105 and 106 ffu [103]. Immunogenicity was detected in 60-65% of the infants and the vaccine conferred protection of 68-87% against severe rotavirus infection and 61-92% against rotavirus hospitalizations [103].

The safety and efficacy study with this vaccine recruited over 60 000 infants in 11 Latin American countries and in Finland, who received two doses of the vaccine at 2 and 4 months of age in a randomized, double-blind, placebo-controlled study [14, 101]. The efficacy of the vaccine was shown to be 85% clinical protection against both rotavirus-associated hospitalization and against severe rotavirus gastroenteritis. The VP7-type specific efficacy was 91% against wildtype G1P[8] strains (homologous to the vaccine), and was 87% against strains bearing only the P[8] antigen (strains G3P[8], G4P[8] and G9P[8]) [14]. Only 14 wild-type strains with a G2P[4] specificity were detected; these strains are of special interest as neither antigen is included in the vaccine.

In the safety cohort, 25 cases of intussusception were reported by active surveillance and hospital record capture methods - 13 cases occurred within 31 days post-administration of any dose with 6 cases in the vaccine group and 7 in the placebo group. The remaining 12 cases occurred after 31 days from administration and up to a year's follow-up, and were detected in the vaccine group (3) and the placebo group (9), indicating that there was no increased risk of intussusception [14].

Following the safety and efficacy clinical data that was generated in a large phase III study in Latin America and Finland [14], the vaccine was licensed by the EMEA in 2006. This licensure is significant because it represents the licensure within the "country of manufacture" and is significant for the international community for possible future procurement. In essence, the vaccine dossier has now been submitted to the WHO for the process of pre-qualification, which would enable developing countries to apply for procurement of the vaccine by the GAVI. This is a crucial step towards introducing the vaccine in some of the poorest countries of the world and where rotavirus mortality is high [5, 8].

Following the recommendation by WHO for the parallel evaluation of new rotavirus vaccines in developing countries in Africa and Asia [19], clinical trials examining specific issues for infants in developing countries (such as the potential interaction of the vaccine with oral poliovirus vaccine (OPV), dose-ranging studies and immunogenicity trials) have been completed in South Africa and Bangladesh [105-107]. Efficacy studies with this vaccine are ongoing in Africa and the results should be available in 2008.

Neonatal human rotavirus strain (RV3)

Neonatal rotavirus infection in Melbourne, Australia was reported to confer clinical protection against subsequent rotavirus disease in infants [26]. This study and other longitudinal surveillance studies [22, 31, 58, 70] indicated that natural infection with a single wild-type rotavirus invariably conferred protection against moderate to severe rotavirus disease upon re-infection. The naturally attenuated neonatal rotavirus strain identified in this study (RV3) was developed as a vaccine candidate due to these observations. The vaccine candidate was shown to be safe and well tolerated in phase I trials in adults, children and infants [108].

A phase II trial administering three doses of vaccine at 105 ffu at 3, 5 and 7 months of age showed an immune response in only 46% of vaccines [109]. However, those infants with an immune response were partially protected against rotavirus disease in the 2nd year, supporting the observation that this strain offered protection after natural infection. The vaccine strain has been adapted to a WHO-approved Vero cell line and produced at a higher titer, and further clinical trials and development with BioFarma, Indonesia are planned (Graeme Barnes, personal communication).

Naturally occurring neonatal bovine-human reassortant strains

Neonatal rotavirus strains identified in India also conferred protection against subsequent rotavirus disease [30]. Strain 116E was identified to be a naturally occurring reassortant strain (G9P8[11]), between bovine and human rotaviruses with only the VP4 gene derived from a bovine rotavirus. A second naturally occurring bovine-human rotavirus strain in neonates was detected in Bangalore. Strain I321 carries G10P8[11] specificity and is predominantly a bovine strain, with only two human rotavirus non-structural proteins present [110]. These strains are being developed further as vaccine candidates by an international consortium consisting of Indian and US collaborators [110].

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