The success of live-attenuated oral rotavirus vaccines (ORVs) in high-income countries has been extraordinary. In this issue of Pediatrics, Maguire et al1  provide an important addition to this literature with an analysis of Rotarix (GlaxoSmithKline, Brentford, United Kingdom) vaccine effectiveness (VE) and rotavirus epidemiology among children in New South Wales, Australia, from 2010 to 2017 (including during a 2017 outbreak). They found high 1-year VE of 89.5%, which decreased to 77.0% among those vaccinated 5 to 10 years previously. The median age of infection increased from 3.9 to 7.1 years over the study period. Interestingly, during the 2017 outbreak, the emerging equine-like G3P[8] and novel G8P[8] strains predominated in most age groups.

Rotaviruses are the leading global cause of dehydrating acute gastroenteritis (AGE) in young children.2  Rotaviruses are segmented, double-stranded RNA viruses categorized according to the structural proteins VP7 and VP4, which define G and P genotypes, respectively. The introduction of Rotarix and RotaTeq (Merck & Co, Inc, Kenilworth, NJ) into national immunization programs in the mid-2000s led to dramatic, sustained reductions in rotavirus incidence, hospitalizations for all-cause AGE and rotavirus-associated gastroenteritis (RVGE), and diarrheal mortality.3  High VE (≥80%) in preventing RVGE hospitalizations among children younger than 5 years and evidence of herd immunity are consistently demonstrated in high-income countries,4,5  where today’s pediatric trainees may complete residency without having diagnosed a single case of proven RVGE. This would have been unheard of scarcely a decade ago.

The Australian experience has been consistent with those in other high-income countries. Therefore, demonstration of high VE in New South Wales, even during an outbreak involving rare strains, is welcome but not unexpected. Hospitalizations for AGE in young children decreased by 71% after ORV introduction in Australia, where estimated ORV efficacy is 84% to 94%.68  In the current study, VE was highest in infants who received the full 2-dose schedule, underscoring the importance of complete and timely immunization.

Unique to Australia was the national introduction of ORVs in 2007 but with state-level implementation of either Rotarix or RotaTeq. This arrangement enabled a fascinating natural experiment of VE and strain selection. The authors hypothesized that selective pressure due to Rotarix, an attenuated G1P[8] strain, may explain the emergence of novel equine-like G3P[8] and G8P[8] strains. Their data support previous observations that states using Rotarix experienced a shift in predominance from G1P[8] to equine-like G3P[8] and G2P[4] strains, whereas states using RotaTeq (a pentavalent formulation of reassortant human G1, G2, G3, G4, and P[8] viruses on bovine backbone) experienced a shift to G12P[8] strains.9  A similar pattern occurred in the United States, where RotaTeq predominates,10  and in both regions, strain predominance fluctuated until G12P[8] establishment. Thus, vaccine pressure appears to affect strain predominance, which may depend on time since introduction, and potentially enables the emergence of novel strains such as G8P[8]. Despite this, large-scale strain replacement has not been demonstrated in rotaviruses, in contrast to the development of pneumococcal serotype replacement that was seen after pneumococcal conjugate vaccine introduction. Similarly, there has been no evidence of widespread vaccine escape due to antigenic drift or shift, as occurs with another important segmented RNA virus, influenza A. Ample evidence indicates robust cross-protection to diverse rotavirus genotypes after vaccination, and overall VE remains high, irrespective of strain diversity.11,12  As noted by the authors, genotype-specific VE estimates will help elucidate rotavirus evolution and vaccine impact. As the Australian natural experiment continues after the nationwide shift to Rotarix in 2017, it will be interesting indeed to see if all states converge toward a similar pattern of strain diversity as in New South Wales from 2010 to 2017.

Another important finding was the shifting age-related epidemiology of infection. The increase in the median age of infection likely reflects effective vaccination in younger children because those older than 10 years never received ORVs. Although VE in children 5 to 10 years postvaccination was still high at 77%, this nevertheless was a 20% decrease compared with VE in children vaccinated within the previous year, suggesting waning immunity. As the authors suggest, immune boosting in older individuals is likely decreasing because of fewer natural exposures due to decreased rotavirus burden in a highly vaccinated population. This may herald an evolving shift in peak RVGE risk to older children. Ongoing monitoring of health care access and use, lost school days (including among older children), and associated societal costs is warranted, even if rotavirus burden in older children due to waning immunity seems unlikely to reach pre–vaccine era levels, which were not insignificant.13 

In this context, it may be tempting to conclude that rotavirus is no longer a significant public health challenge. However, despite the success of ORVs, substantial barriers remain to eliminating the threat of RVGE. First, ORV coverage lags behind that of other vaccines,14  a consistent pattern in all countries using ORVs. Second, many countries have yet to introduce ORVs into national immunization programs. In certain settings, cold-chain capacity, cost, and product availability are clear obstacles. Hopefully, World Health Organization prequalification in 2018 of 2 newer Indian vaccines, Rotavac (Bharat Biotech, Hyderabad, India) and RotaSIL (Serum Institute of India, Pune, India), may help mitigate these challenges. Unfortunately, lingering concerns about safety, impact, or cost-effectiveness may also be delaying ORV introductions despite abundant evidence strongly supporting favorability. For example, fears persist about intussusception, which was associated with the now-withdrawn RotaShield (Wyeth Laboratories, Inc., Marietta, PA) vaccine. But current ORVs have a much lower intussusception risk that is dwarfed by their proven benefits. In the Unites States, 45 to 213 potential cases of vaccine-associated intussusception would compare with ∼53 000 averted hospitalizations for RVGE.15  Finally, ORVs are far less effective in low-income countries, where the burden of severe disease and mortality is greatest.3,16,17  Too many children in the world’s poorest countries thus remain unprotected even after vaccination.

Ultimately, 100 million children representing 75% of the world’s infants remain unvaccinated in 2018, with >128 000 pediatric deaths yearly due to RVGE.18,19  Improving vaccine access and coverage and solving the riddle of ORV underperformance in low-income countries are urgent priorities, which may ultimately require next-generation oral and/or parenteral vaccines, a number of which are under development and in clinical trials. In addition, because the emergence of novel strains of disease-causing pathogens is always a possibility, vigilance in rotavirus surveillance, including genotype assessment, should remain a priority for public health programs.

Opinions expressed in these commentaries are those of the authors and not necessarily those of the American Academy of Pediatrics or its Committees.

FUNDING: No external funding.

COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2019-1024.

AGE

acute gastroenteritis

ORV

oral rotavirus vaccine

RVGE

rotavirus-associated gastroenteritis

VE

vaccine effectiveness

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.