Next Generation of Vaccines

There are a variety of vaccines currently in development around the world. The largest ongoing trails are testing new vaccines developed by Merck and GlaxoSmithKline that attempt to replicate the efficacy of RotaShield^® without inducing similar complications.

Predicting whether intussusception will be induced by the new generation of rotavirus vaccines is difficult since the connection between this uncommon side effect and vaccination with RotaShield^® is still poorly understood.

Other techniques for vaccination are being explored, including DNA vaccination and attempts to develop a vaccine based on a neonatal strain of rotavirus that confers protection after asymptomatic infection.

RotaTeq^®

Paul Offit at The Children's Hospital of Philadelphia developed a vaccine based on a bovine strain of rotavirus (WC-3). Merck is currently running Phase III trials of a modified version of his quadravalent reassortant vaccine.

Aiming to avoid the adverse affects that RotaShield^® was associated with, the vaccine is based on a bovine strain of rotavirus. The bovine strain was chosen because it replicates less prolifically in the human gastrointestinal tract than the simian strain used for the tetravalent rhesus reassortant vaccine. [1] Each of the five reassortants consists of the genetic backbone of the bovine virus with an inserted gene coding for a different human rotavirus surface protein. The inserted genes were selected to represent a broad range of serotypes in order to elicit protection against a wide variety of strains.

Genes coding for four VP7 proteins and one VP4 protein are included in the reassortants. Human serotypes G1, G2, G3 and G4 are represented by the four VP7 proteins, and serotype P1a is represented by the VP4 protein. [2]

Initial trials of a similar live quadrivalent human-bovine reassortant vaccine demonstrated promising protection against rotavirus infection. [3] Differing from the Merck vaccine only by the exclusion of serotype G4, this vaccine's results likely mirror the protection that RotaTeq® will afford.

The quadrivalent vaccine, which was delivered to vaccinees in three oral doses at 2, 4, and 6 months of age (identical to the Merck vaccine delivery schedule), showed 74.6% efficacy against any rotavirus infection and 100% efficacy against severe rotavirus infection. No increase in diarrhea, vomiting, fever or irritability was reported as compared to the recipients of the placebo.

The immunogenicity of the quadrivalent vaccine was reflected in an increased ratio of rotavirus specific IgA to total IgA as measured in the vaccinee's stool. [3]

Rotarix^®

Initiallly developed by Richard Ward and David Bernstien, vaccine 89-12 is a live monovalent attenuated vaccine. GlaxoSmithKline Biologicals is currently developing and testing a vaccine derived from vaccine 89-12 (developed by ADVANT Immunotherapies) under the name Rotarix®. Phase III trials were initiated in the summer of 2003 and the vaccine may be licensed outside of the United States in the coming months[4].

Basing the vaccine on a human strain as opposed to a simian strain is expected to prevent the complication of intussusception. Because there is no link between intussusception and natural infection with rotavirus[5], researchers reason that an attenuated human virus should not provoke the unusual side effect.

The vaccine comes from a G1, P1a strain of rotavirus isolated from a child in Cincinnati, Ohio. The vaccine strain, RIX4414, was attenuated by tissue culture passaging of the parent strain. It is delivered orally in a calcium carbonate buffer that protects the attenuated virus from inactivation by stomach acids. [5]

In small trials thus far the vaccine has shown 76% efficacy against any rotavirus gastroenteritis, 83% efficacy against severe rotavirus gastroenteritis and 100% efficacy against rotavirus gastroenteritis requiring medical intervention. [5]

A monovalent vaccine approach relies on the ability of infection with one serotype to provide protection against infection by other serotypes. Studies show that two infections with rotavirus, even repeated infection with the same serotype, confer immunity against subsequent severe infection. [5] Rotarix^® is delivered orally, in two doses at 2 and 4 months of age before maternal antibody protection is lost.

When compared to RotaTeq®, Rotarix® has a higher incidence of low grade fever as a side effect of vaccination. [5] However, no other symptoms, such as diarrhea or vomitting were noted.

Another important factor in vaccine development is fitting a new vaccine into the current vaccination schedule. Rotarix® can be administered at the same time as DTPw/HB/HiB and DTPa comination vaccines without interference. There is some data that suggests that concurrent admistration of the first dose of Rotarix® and Oral Polio Vaccine (OPV) reduces immunogenicity or the rotavirus vaccine, but upon administration of the second dose, similar protection is acheived. [7]

Monovalent Lamb Vaccine

The only vaccine that is currently licensed is in use in China.   Developed by Zhi-Sheng Bai at the Lanzhou Institute, the attenuated monovalent vaccine is based on a strain of lamb rotavirus.   Similar to Rotarix^®, the lamb rotavirus strain was attenuated by passage in cell culture.  

The lamb vaccine is classified as serotype P[10], G12. It is delivered as a single dose, between the ages of 2-24 months.

The vaccine has been proven to be safe and immunogenic (with 61% of vaccinees developing neutralizing antibody responses), but efficacy results of the Phase II trails have yet to be published.[6]

Other Vaccines in Preclinical Trials

Phase I trials are currently underway to explore the possibility of developing a vaccine based on a neonatal strain of rotavirus that was discovered by Ruth Bishop in Melbourne, Australia. RV3, which was found to asymptomatically infect neonates provides heterotypic protection against severe rotavirus gastroenteritis from serotypes G1 and G2.

Two naturally occuring human-bovine reassortant strains were isolated from neonates in New Delhi (the 116E strain) and Bangalore (the I321strain). These strains are currently being developed for clinical trials by Bharat Biotech and AIIMS with support from the CDC and the Programme for Appropriate Technology in Health (PATH).

A series of alternate human-bovine reassortant vaccines are also currently being developed by AZ Kapikian supported by NIAID and NIH.

Overview of Rotavirus Vaccines

Table from Kirkwood & Buttery [6]