Reactogenicity and immunogenicity of a high-titer rhesus rotavirus-based quadrivalent rotavirus vaccine

Flores, Jorge; Pérez‐Schael, Irene; Blanco, Mireya González; Rojas, Ana M.; Alfonzo, Edgar; Crespo, Ilirie; Cunto, Walter; Pittman, A L; Kapikian, Albert Z.

doi:10.1128/jcm.31.9.2439-2445.1993

Cited by 43 publications

(6 citation statements)

References 21 publications

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“…As shown, infection with heterologous strains was relatively efficient at inducing serum IgG responses, and the responses were relatively similar over the immunizing dosage range administered. Similar observations have been made in humans (1,5,13). At all dosages of heterologous virus delivered, a relatively broad range of serum responses was detected ( Table 3).…”

Section: Discussionsupporting

confidence: 85%

Comparison of mucosal and systemic humoral immune responses and subsequent protection in mice orally inoculated with a homologous or a heterologous rotavirus

Feng

Burns

Bracy

et al. 1994

J Virol

175

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Rotaviruses are the single most important cause of severe diarrhea in young children worldwide, and vaccination is probably the most effective way to control the disease. Most current live virus vaccine candidates are based on the host range-restricted attenuation of heterologous animal rotaviruses in humans. The protective efficacy of these vaccine candidates has been variable. To better understand the nature of the heterologous rotavirus-induced active immune response, we compared the differences in the mucosal and systemic immune responses generated by heterologous (nonmurine) and homologous (murine) rotaviruses as well as the ability of these infections to produce subsequent protective immunity in a mouse model. Sucking mice were orally inoculated with a heterologous simian or bovine rotavirus (strain RRV or NCDV) or a homologous murine rotavirus (wild-type or tissue culture-adapted) strain EHP at various doses. Six weeks later, mice were challenged with a virulent murine rotavirus (wild-type strain ECW) and the shedding of viral antigen in feces was quantitated. Levels of rotavirus-specific serum immunoglobulin G (IgG) and fecal IgA prior to challenge were measured and correlated with subsequent viral shedding or protection. Heterologous rotavirus-induced active protection was highly dependent on the strain and dose of the virus tested. Mice inoculated with a high dose (107 PFU per mouse) of RRV were completely protected, while the protection was diminished in animals inoculated with NCDV or lower doses of RRV. The ability of a heterologous rotavirus to stimulate a detectable intestinal IgA response correlated with the ability of the virus to generate protective immunity. Serum IgG titer did not correlate with protection. Homologous rotavirus infection, on the other hand, was much more efficient at inducing both mucosal and systemic immune responses as well as protection regardless of the virulence of the virus strain or the size of the immunizing dose.

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Section: Discussionsupporting

confidence: 85%

Comparison of mucosal and systemic humoral immune responses and subsequent protection in mice orally inoculated with a homologous or a heterologous rotavirus

Feng

Burns

Bracy

et al. 1994

J Virol

175

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“…The safety and reactogenicity profiles were similar to those of the RRV vaccine. VP7 serotype 1-to 4-specific responses were induced in approximately one-third to one-half of vaccinees (41,81,110). Three doses of vaccine (10 5 or 10 6 PFU) induced a significantly greater number of seroresponses to each of the four serotypes than did single dose of these vaccines (41).…”

Section: Human-rhesus Rotavirus Reassortant Vaccinesmentioning

confidence: 96%

“…After phase 1 studies with monovalent reassortants were completed, studies of multivalent preparations were begun. A quadrivalent vaccine containing 10 4 PFU of each of the three human-RRV reassortants representing VP7 serotypes 1, 2, and 4 and of RRV (VP7 serotype 3) was shown to be safe and well tolerated in young infants, inducing a similar rate of febrile reactions to that noted with 10 4 PFU of RRV or monovalent reassortant vaccines (41,43,81,110,111). Although over 70% of vaccinated infants developed a serologic response by IgA ELISA, increases in levels of neutralizing antibody to each of the four VP7 serotypes contained in the vaccine were detected in only 32 to 58% of infants and 17 to 39% of infants in two studies in Venezuela (43,111).…”

Section: Human-rhesus Rotavirus Reassortant Vaccinesmentioning

confidence: 97%

Rotavirus vaccines: an overview

1996

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Rotavirus vaccine development has focused on the delivery of live attenuated rotavirus strains by the oral route. The initial "Jennerian" approach involving bovine (RIT4237, WC3) or rhesus (RRV) rotavirus vaccine candidates showed that these vaccines were safe, well tolerated, and immunogenic but induced highly variable rates of protection against rotavirus diarrhea. The goal of a rotavirus vaccine is to prevent severe illness that can lead to dehydration in infants and young children in both developed and developing countries. These studies led to the concept that a multivalent vaccine that represented each of the four epidemiologically important VP7 serotypes might be necessary to induce protection in young infants, the target population for vaccination. Human-animal rotavirus reassortants whose gene encoding VP7 was derived from their human rotavirus parent but whose remaining genes were derived from the animal rotavirus parent were developed as vaccine candidates. The greatest experience with a multivalent vaccine to date has been gained with the quadrivalent preparation containing RRV (VP7 serotype 3) and human-RRV reassortants of VP7 serotype 1, 2, and 4 specificity. Preliminary efficacy trial results in the United States have been promising, whereas a study in Peru has shown only limited protection. Human-bovine reassortant vaccines, including a candidate that contains the VP4 gene of a human rotavirus (VP4 serotype 1A), are also being studied.

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“…Although the role of serotype-specific neutralizing antibody in immunity from rotavirus infection in children remains unclear, antibodies to VP4 and VP7 are each independently associated with protection against rotavirus challenge in various animal models (1,32,34,36,46,47). The lack of consistent protective efficacy observed in early field trials of bovine and simian rotavirus vaccines in humans was attributed to the induction of serotypespecific immunity that did not protect against heterotypic strains of circulating rotavirus (21,27,38). Multivalent simian and bovine reassortant vaccines were developed to overcome this deficiency (10,27).…”

mentioning

confidence: 99%

Heterotypic Protection and Induction of a Broad Heterotypic Neutralization Response by Rotavirus-Like Particles

Crawford

Estes

Ciarlet

et al. 1999

J Virol

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The recognition that rotaviruses are the major cause of life-threatening diarrheal disease and significant morbidity in young children has focused efforts on disease prevention and control of these viruses. Although the correlates of protection in children remain unclear, some studies indicate that serotype-specific antibody is important. Based on this premise, current live attenuated reassortant rotavirus vaccines include the four predominant serotypes of virus. We are evaluating subunit rotavirus vaccines, 2/6/7-VLPs and 2/4/6/7-VLPs, that contain only a single VP7 of serotype G1 or G3. In mice immunized parenterally twice, G3 virus-like particles (VLPs) induced a homotypic, whereas G1 VLPs induced a homotypic and heterotypic (G3) serum neutralizing immune response. Administration of three doses of G1 or G3 VLPs induced serum antibodies that neutralized five of seven different serotype test viruses. The inclusion of VP4 in the VLPs was not essential for the induction of heterotypic neutralizing antibody in mice. To confirm these results in another species, rabbits were immunized parenterally with two doses of 2/4/6/7-VLPs containing a G3 or G1 VP7, sequentially with G3 VLPs followed by G1 (G3/G1) VLPs, or with live or psoralen-inactivated SA11. High-titer homotypic serum neutralizing antibody was induced in all rabbits, and low-level heterotypic neutralizing antibody was induced in a subset of rabbits. The rabbits immunized with the G1 or G3/G1 VLPs in QS-21 were challenged orally with live G3 ALA rotavirus. Protection levels were similar in rabbits immunized with homotypic G3 2/4/6/7-VLPs, heterotypic G1 2/4/6/7-VLPs, or G3/G1 2/4/6/7-VLPs. Therefore, G1 2/4/6/7-VLPs can induce protective immunity against a live heterotypic rotavirus challenge in an adjuvant with potential use in humans. Following challenge, broad serum heterotypic neutralizing antibody responses were detected in rabbits parenterally immunized with G1, G3/G1, or G3 VLPs but not with SA11. Immunization with VLPs may provide sufficient priming of the immune system to induce protective anamnestic heterotypic neutralizing antibody responses upon subsequent rotavirus infection. Therefore, a limited number of serotypes of VLPs may be sufficient to provide a broadly protective subunit vaccine.

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Reactogenicity and immunogenicity of a high-titer rhesus rotavirus-based quadrivalent rotavirus vaccine

Cited by 43 publications

References 21 publications

Comparison of mucosal and systemic humoral immune responses and subsequent protection in mice orally inoculated with a homologous or a heterologous rotavirus

Comparison of mucosal and systemic humoral immune responses and subsequent protection in mice orally inoculated with a homologous or a heterologous rotavirus

Rotavirus vaccines: an overview

Heterotypic Protection and Induction of a Broad Heterotypic Neutralization Response by Rotavirus-Like Particles

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