Human rotavirus vaccine Rotarix™ provides protection against diverse circulating rotavirus strains in African infants: a randomized controlled trial

Rotavirus is the single most important cause of severe acute gastroenteritis worldwide in children under the age of five. The World Health Organization (WHO) estimates that rotavirus is associated with approximately 527,000 deaths globally, the majority of which (>85%) occur in young children in the developing countries of Asia and Africa [1, 2]. Recently, WHO made a global recommendation for rotavirus immunization in all infants [3] based on the efficacy data generated in developing countries with both commercial rotavirus vaccines namely, Rotarix™ (GlaxoSmithKline Biologicals) and Rotateq™ (Merck and Co., Inc) [4‐6].

In the pivotal efficacy studies conducted with these two rotavirus vaccines across Europe, Latin America, Asia and the USA, efficacy (ranging between 85% to 98%) was demonstrated against severe rotavirus gastroenteritis [7, 8]. Additional clinical trials have confirmed the efficacy of the monovalent G1P[8] human rotavirus vaccine, Rotarix™ (GSK Biologicals, Rixensart, Belgium), against multiple rotavirus strains found to occur commonly in human infants [4, 9‐11]. A pooled analysis of the clinical studies performed with Rotarix™ also demonstrated heterotypic protection of this vaccine against various human rotaviruses [12]. Nevertheless, uncertainty remains regarding the extent of cross protection provided by Rotarix™, particularly against strains that bear neither the G1 nor the P[8] antigens.

Rotaviruses are double stranded RNA (dsRNA) viruses composed of an outer capsid, an inner capsid and a core that houses the 11 segments of dsRNA. The viruses carry two neutralization antigens located on the outer capsid, which are known to elicit the production of serotype-specific neutralizing immune response in the host, and are considered important in vaccine development [13]. The outer capsid antigens – VP4 (P-type) and VP7 (G-type) - are categorized into various “genotypes” based on the molecular characterization of the genes encoding these two outer capsid proteins [14].

Among rotavirus strains, many combinations of the G- and P-types are possible, although a limited number have been commonly identified among human rotaviruses. So, G1P[8] is the most common strain circulating globally representing more than 50% of all human rotavirus strains, and G3P[8], G4P[8], G9P[8] and G2P[4] also occur commonly [14]. G2P[4] rotaviruses are distinct to the monovalent vaccine on both antigens, and have garnered special interest. These strains seem to appear in a cyclic nature in the human population, emerging as the dominant strain every 3–4 years [15, 16].

Nevertheless, rotavirus strain diversity remains a complex issue for a number of reasons. Firstly, there are well-recognized geographic differences in the distribution and circulation of wild-type rotaviruses. G8 strains have had a peculiar predilection for Africa and occur much more frequently here than in other regions [17‐21]; similarly G5 strains circulated widely in Latin America [14, 22] and G10 strains were more common in India [23]. Secondly, new strains emerge through natural molecular evolution to appear in the human population, as demonstrated by the recent appearance of G12 strains [24, 25]. Finally, strains also evolve through small “antigenic drift” changes in one of the outer capsid genes, thus eluding typing by the reverse-transcription polymerase chain reaction (RT-PCR) primers [18, 26, 27]. The VP4 types show similar diversity, although only three P-types (P[4], P[6] and P[8]) are common in human rotaviruses. In Africa, the P[6] type is identified much more commonly and can represent more than 50% of strains from symptomatic infections [28, 29].

Epidemiological data have shown that Africa harbors a diverse range of rotavirus types, from the most common G1 type to the unusual G8, G9, G10 and G12 [28‐30] types. In a large, randomized controlled trial conducted in Malawi and South Africa, Rotarix™ was 61.2% efficacious in protecting infants from severe rotavirus gastroenteritis due to this wide range of diverse strains [4].

In the current paper we describe the rotavirus types identified in the phase III African trial and the efficacy of the monovalent G1P[8] human rotavirus vaccine in preventing severe rotavirus gastroenteritis caused by various circulating G- and P-rotavirus types.

Africa presents unique challenges for rotavirus immunization. First, the continent carries the highest burden of rotavirus mortality, where 12 of the 13 countries with greatest mortality rates per capita are located [2, 34], and more than 250,000 children perish annually due to rotavirus [29, 35]. Rotavirus vaccines are urgently needed in this region which would make a substantial contribution in reducing childhood deaths and hospitalizations due to rotavirus [36]. Most GAVI (Global Alliance for Vaccines and Immunization)-eligible countries are concentrated in Africa and the lowest global immunization coverage is also recorded here [37]. Given the high burden of rotavirus disease in Africa, the WHO recommends the early administration of rotavirus vaccines with the first two immunizations at 6 and 10 weeks of age [1].

Secondly, rotavirus strain diversity is extremely high in Africa with some novel G- and P-types circulating commonly [17, 27‐30]. Besides the globally emerging novel rotavirus strains, G9 and G12, which also occur commonly in Africa [21, 24, 25, 38, 39], G8 strains are frequently identified and seem to have an unusual affinity for Africa [17‐21]. Furthermore, strains with the P[6] genotype circulate commonly in young African children with symptomatic rotavirus infection [17, 28].

The wide circulation of diverse and unusual rotavirus strains in the region, emphasizes the importance of demonstrating cross-protective efficacy of the monovalent rotavirus vaccine, Rotarix™ in preventing severe gastroenteritis [24, 28, 40]. Previous study has demonstrated that heterotypic protection may be due to the expression of serologically or genotypically identical proteins other than those encoded by the different G-types [41]. The immune response to the VP4 antigen has been demonstrated to be significant [42], and there are cross-reactive epitopes on the VP4 protein [43]. The relative lack of diversity among P-types [42] when compared with the G types, may aid in heterotypic protection as suggested previously [43]. In addition, protection may be offered via immune effector mechanisms other than neutralizing antibody [44].

In the present paper, in addition to the common G1 and P[8] types, we observed five G types (G2, G3, G8, G9 and G12) and two P types (P[4] and P[6]) in circulation during the study period. Importantly, the G8 and G12 types have not been observed in earlier efficacy studies providing the opportunity to assess vaccine efficacy against these novel types [9‐11]. Similarly, the numbers of strains bearing the P[4] genotype with various G-types, all heterotypic to the G1P[8] vaccine strain, enable an assessment of vaccine efficacy against truly heterotypic strains. The strain combinations used to generate the results include 8 G2P[4] strains, 19 G8P[4] strains and a single G8P[6], and 23 strains bearing G12P[6] specificity.

The overall vaccine efficacy of the monovalent rotavirus vaccine in preventing severe rotavirus gastroenteritis in African infants was previously reported as 61.2% (95% CI: 44%; 73.2%) [4]. G1 wild-type was the predominant circulating rotavirus type isolated from 23 severe rotavirus gastroenteritis episodes in placebo group. Interestingly, the pattern of circulation of rotavirus types differed considerably between South Africa and Malawi during the study period. Unlike South Africa, where G1 was predominantly circulating (isolated from 18 severe rotavirus gastroenteritis episodes in placebo group) similar to worldwide epidemiology, this was not the case in Malawi, where G1 wild-type strains were the lowest seen in more than a decade of surveillance [45]. In Malawi, G12 was the predominant rotavirus type (isolated from 13 severe rotavirus gastroenteritis episodes in placebo group), as observed in an earlier study by Cunliffe et al, where G12 was identified as a newly emerging rotavirus type in Malawi [24]. Furthermore, G9 was circulating only in Malawi during the study period and hence the overall efficacy data on G9 rotavirus type reflected the Malawi-specific situation.

We can anticipate that the monovalent rotavirus vaccine will provide protection against the circulating rotavirus types that shared either the G or the P type with the vaccine strain (homotypic protection). However, the G2 and G8 types were all circulating in combination with P[4] type (with a single strain bearing G8P[6] specificity), sharing neither the G or the P type with the vaccine strain. It is therefore important to note that significant protection was afforded by the vaccine against severe gastroenteritis caused by these dually heterotypic rotavirus types (vaccine efficacy against G2: 79.2% [95% CI: 8.9%; 96.5%; p -value = 0.017]; vaccine efficacy against G8: 64.4% [95% CI: 17.1%; 85.2%; p-value 0.010]; vaccine efficacy against P[4]: 70.9% [95% CI: 37.5%; 87.0%]). This is an important observation as the earlier efficacy studies showed limited heterotypic protection [9‐11], and there has been some suggestion that the monovalent vaccine may not confer cross protection against non-vaccine strains.

These data are encouraging because with the diversity of the rotavirus types in circulation and the global emergence of new strains in the human population, homotypic protection alone will be unlikely to provide complete protection against severe rotavirus gastroenteritis. Heterotypic protection of the rotavirus vaccine is important to effectively reduce the rotavirus disease burden.

Rotavirus surveillance efforts are needed in Africa to elucidate the burden of disease and the strain diversity in the region; but importantly to provide a platform against which the impact of the vaccines can be assessed once they are introduced. Rotavirus surveillance after the introduction of routine vaccination could further explore the concept of heterotypic protection in a real-life setting.