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Comparative analysis of pentavalent rotavirus vaccine strains and G8 rotaviruses identified during vaccine trial in Africa.

Heylen E, Zeller M, Ciarlet M, Lawrence J, Steele D, Van Ranst M, Matthijnssens J - Sci Rep (2015)

Bottom Line: RotaTeqTM is a pentavalent rotavirus vaccine based on a bovine rotavirus genetic backbone in vitro reassorted with human outer capsid genes.Because RotaTeqTM possesses a bovine genetic backbone, the high vaccine efficacy against G8 strains might be partially explained by the fact that all these strains contain a complete or partial bovine-like backbone.Altogether, this study supports the hypothesis that gene segments other than VP7 and VP4 play a role in vaccine-induced immunity.

View Article: PubMed Central - PubMed

Affiliation: KU Leuven - University of Leuven, Department of Microbiology and Immunology, Laboratory for Clinical and Epidemiological virology, Rega Institute for Medical Research, Leuven, Belgium.

ABSTRACT
RotaTeqTM is a pentavalent rotavirus vaccine based on a bovine rotavirus genetic backbone in vitro reassorted with human outer capsid genes. During clinical trials of RotaTeqTM in Sub-Saharan Africa, the vaccine efficacy over a 2-year follow-up was lower against the genotypes contained in the vaccine than against the heterotypic G8P[6] and G8P[1] rotavirus strains of which the former is highly prevalent in Africa. Complete genome analyses of 43 complete rotavirus genomes collected during phase III clinical trials of RotaTeqTM in Sub-Saharan Africa, were conducted to gain insight into the high level of cross-protection afforded by RotaTeqTM against these G8 strains. Phylogenetic analysis revealed the presence of a high number of bovine rotavirus gene segments in these human G8 strains. In addition, we performed an in depth analysis on the individual amino acid level which showed that G8 rotaviruses were more similar to the RotaTeqTM vaccine than non-G8 strains. Because RotaTeqTM possesses a bovine genetic backbone, the high vaccine efficacy against G8 strains might be partially explained by the fact that all these strains contain a complete or partial bovine-like backbone. Altogether, this study supports the hypothesis that gene segments other than VP7 and VP4 play a role in vaccine-induced immunity.

No MeSH data available.


Related in: MedlinePlus

Phylogenetic dendrograms based on the nucleotide sequences of VP6, VP1, VP3 and NSP2.Bootstrap values (500 replicates) above 70 are shown. G8 RVA strains analysed in this study are indicated with a triangle (colour code according to Fig. 1), selected non-G8 strains were indicated with a black triangle, viruses present in RV5 are indicated with a diamond.
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f3: Phylogenetic dendrograms based on the nucleotide sequences of VP6, VP1, VP3 and NSP2.Bootstrap values (500 replicates) above 70 are shown. G8 RVA strains analysed in this study are indicated with a triangle (colour code according to Fig. 1), selected non-G8 strains were indicated with a black triangle, viruses present in RV5 are indicated with a diamond.

Mentions: The 9 RVA gene segments encoding VP1-3, VP6, NSP1-5/6 of the six characterized West-African G8P[6] strains can be divided into 3 ‘tree-groups’, based on their clustering in the phylogenetic trees. The first ‘tree-group’ contains the VP1, VP6, VP3 and NSP2 segments of the West-African strains. Figure 3 shows that strains Ghana-113, Ghan-149, Mali-039, Mali-048, Mali-119 and Mali-135 are only distantly related to typical human DS-1-like RVA strains, which are indicated by red bars in the phylogenetic dendrograms. Instead, these genes cluster within clusters containing bovine or bovine-like human RVAs, indicated by blue bars in the phylogenetic trees. For example, for VP6, the strains from Mali are closely related to RVAs isolated from an antelope and a cow, and to the South-African strain RVA/Human-wt/ZAF/2371WC/2008/G9P[8] which has several gene segments with close similarity to artiodactyl RVAs34. The three Ghanaian strains are clustering together with strains RVA/Cow-wt/IND/1970/2009/GxP[x] and RVA/Pig-wt/IND/HP140/1987/G6P[13], the latter being a porcine strain with a VP6 gene of bovine origin35. The VP1 genes of the West-African RVA strains formed 3 distinct subclusters. The first and second subcluster contained the Ghanaian and Malian G8P[6] strains which were most closely related to RVA/Human-wt/GHA/GH018-08/2008/G8P[6], described to be a human-bovine reassortant virus31. The third cluster contained the G8P[1] strain, clustering most closely to strain RVA/Human-wt/BEL/B1711/2002/G6P[6], an atypical human strain which is believed to be a bovine/human reassortant strain infecting a Belgian child during a trip to Mali36. For VP3, the strains from Mali are most closely related to strain RVA/Human-wt/HUN/BP1062/2004/G8P[14], another atypical human strain which is the result of an interspecies transmission event37. During 2008, at least three different lineages of the M2 genotype circulated in Ghana, as indicated by three distinct Ghanaian clusters within the VP3 tree, showing only 83.0–88.4% nt identity. One cluster only contained non-G8 RVAs, the second cluster contained strain Ghan-059 and the third contained both strains Ghan-149 and Ghan-113. The latter two strains are very closely related to VP3 sequences of GH018-08 and RVA/Human-wt/GHA/GH019-08/2008/G8P[6], showing 99.9% nt similarity31. The tree of NSP2 also showed three distinct Ghanaian clusters. Two of them, which contain the Ghanaian G8 RVAs (Ghan-059 vs. Ghan-149 and Ghan-113), show 87.5% similarity on the nt level and are both subclusters of the N2 genotype not belonging to the typical human N2 cluster (indicated in red in Fig. 3). The four Malian strains are identical to 2371WC (100% nt similarity) and cluster together with unusual human P[14] RVAs indicated a shared ancestry with animal RVAs.


Comparative analysis of pentavalent rotavirus vaccine strains and G8 rotaviruses identified during vaccine trial in Africa.

Heylen E, Zeller M, Ciarlet M, Lawrence J, Steele D, Van Ranst M, Matthijnssens J - Sci Rep (2015)

Phylogenetic dendrograms based on the nucleotide sequences of VP6, VP1, VP3 and NSP2.Bootstrap values (500 replicates) above 70 are shown. G8 RVA strains analysed in this study are indicated with a triangle (colour code according to Fig. 1), selected non-G8 strains were indicated with a black triangle, viruses present in RV5 are indicated with a diamond.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4594120&req=5

f3: Phylogenetic dendrograms based on the nucleotide sequences of VP6, VP1, VP3 and NSP2.Bootstrap values (500 replicates) above 70 are shown. G8 RVA strains analysed in this study are indicated with a triangle (colour code according to Fig. 1), selected non-G8 strains were indicated with a black triangle, viruses present in RV5 are indicated with a diamond.
Mentions: The 9 RVA gene segments encoding VP1-3, VP6, NSP1-5/6 of the six characterized West-African G8P[6] strains can be divided into 3 ‘tree-groups’, based on their clustering in the phylogenetic trees. The first ‘tree-group’ contains the VP1, VP6, VP3 and NSP2 segments of the West-African strains. Figure 3 shows that strains Ghana-113, Ghan-149, Mali-039, Mali-048, Mali-119 and Mali-135 are only distantly related to typical human DS-1-like RVA strains, which are indicated by red bars in the phylogenetic dendrograms. Instead, these genes cluster within clusters containing bovine or bovine-like human RVAs, indicated by blue bars in the phylogenetic trees. For example, for VP6, the strains from Mali are closely related to RVAs isolated from an antelope and a cow, and to the South-African strain RVA/Human-wt/ZAF/2371WC/2008/G9P[8] which has several gene segments with close similarity to artiodactyl RVAs34. The three Ghanaian strains are clustering together with strains RVA/Cow-wt/IND/1970/2009/GxP[x] and RVA/Pig-wt/IND/HP140/1987/G6P[13], the latter being a porcine strain with a VP6 gene of bovine origin35. The VP1 genes of the West-African RVA strains formed 3 distinct subclusters. The first and second subcluster contained the Ghanaian and Malian G8P[6] strains which were most closely related to RVA/Human-wt/GHA/GH018-08/2008/G8P[6], described to be a human-bovine reassortant virus31. The third cluster contained the G8P[1] strain, clustering most closely to strain RVA/Human-wt/BEL/B1711/2002/G6P[6], an atypical human strain which is believed to be a bovine/human reassortant strain infecting a Belgian child during a trip to Mali36. For VP3, the strains from Mali are most closely related to strain RVA/Human-wt/HUN/BP1062/2004/G8P[14], another atypical human strain which is the result of an interspecies transmission event37. During 2008, at least three different lineages of the M2 genotype circulated in Ghana, as indicated by three distinct Ghanaian clusters within the VP3 tree, showing only 83.0–88.4% nt identity. One cluster only contained non-G8 RVAs, the second cluster contained strain Ghan-059 and the third contained both strains Ghan-149 and Ghan-113. The latter two strains are very closely related to VP3 sequences of GH018-08 and RVA/Human-wt/GHA/GH019-08/2008/G8P[6], showing 99.9% nt similarity31. The tree of NSP2 also showed three distinct Ghanaian clusters. Two of them, which contain the Ghanaian G8 RVAs (Ghan-059 vs. Ghan-149 and Ghan-113), show 87.5% similarity on the nt level and are both subclusters of the N2 genotype not belonging to the typical human N2 cluster (indicated in red in Fig. 3). The four Malian strains are identical to 2371WC (100% nt similarity) and cluster together with unusual human P[14] RVAs indicated a shared ancestry with animal RVAs.

Bottom Line: RotaTeqTM is a pentavalent rotavirus vaccine based on a bovine rotavirus genetic backbone in vitro reassorted with human outer capsid genes.Because RotaTeqTM possesses a bovine genetic backbone, the high vaccine efficacy against G8 strains might be partially explained by the fact that all these strains contain a complete or partial bovine-like backbone.Altogether, this study supports the hypothesis that gene segments other than VP7 and VP4 play a role in vaccine-induced immunity.

View Article: PubMed Central - PubMed

Affiliation: KU Leuven - University of Leuven, Department of Microbiology and Immunology, Laboratory for Clinical and Epidemiological virology, Rega Institute for Medical Research, Leuven, Belgium.

ABSTRACT
RotaTeqTM is a pentavalent rotavirus vaccine based on a bovine rotavirus genetic backbone in vitro reassorted with human outer capsid genes. During clinical trials of RotaTeqTM in Sub-Saharan Africa, the vaccine efficacy over a 2-year follow-up was lower against the genotypes contained in the vaccine than against the heterotypic G8P[6] and G8P[1] rotavirus strains of which the former is highly prevalent in Africa. Complete genome analyses of 43 complete rotavirus genomes collected during phase III clinical trials of RotaTeqTM in Sub-Saharan Africa, were conducted to gain insight into the high level of cross-protection afforded by RotaTeqTM against these G8 strains. Phylogenetic analysis revealed the presence of a high number of bovine rotavirus gene segments in these human G8 strains. In addition, we performed an in depth analysis on the individual amino acid level which showed that G8 rotaviruses were more similar to the RotaTeqTM vaccine than non-G8 strains. Because RotaTeqTM possesses a bovine genetic backbone, the high vaccine efficacy against G8 strains might be partially explained by the fact that all these strains contain a complete or partial bovine-like backbone. Altogether, this study supports the hypothesis that gene segments other than VP7 and VP4 play a role in vaccine-induced immunity.

No MeSH data available.


Related in: MedlinePlus