Our analysis demonstrates that if first dose of rotavirus vaccine is restricted to children 14 wk of age or younger, rotavirus vaccines would prevent about 155,800 of the 453,000 rotavirus deaths occurring in children <5 y of age annually worldwide while resulting in 253 intussusception deaths. While most of the gap in preventable rotavirus deaths is due to the moderate efficacy of the vaccines in high mortality settings, the current age restrictions on rotavirus vaccination also contribute by potentially excluding nearly 21%–25% of the world's children, those with the highest risk of rotavirus mortality, from receiving these vaccines. Lifting the age restriction for the first dose of rotavirus vaccination would save an additional 47,200 lives yearly and would result in an additional 294 intussusception deaths, for an incremental benefit of saving 154 lives for each excess intussusception death caused.
In the past 5 y, with the introduction of rotavirus vaccines in nearly 30 countries worldwide, substantial experience has been gained with regard to the safety and effectiveness of these vaccines in the real-world setting, including against deaths 
. Moreover, clinical trials for these vaccines have documented their efficacy in target populations of Asia and Africa, where majority of the rotavirus deaths occur. Given these encouraging data, the ability of the vaccines to reach children with the highest mortality will be a major determinant of their life-saving impact.
Our base estimates are conservative, erring on the side of overestimating vaccine risk for four reasons. First, over 45 publications have documented remarkable declines in severe diarrhea and rotavirus disease, including deaths, since their introduction in national immunization programs worldwide 
. Many of these studies from different locations have demonstrated significant declines in unvaccinated members of the community, indicating indirect benefits of vaccination that we did not account for in our analysis 
. Second, because of interference from circulating transplacental antibodies during the first several months of life, immune response to vaccine and thus efficacy is likely to be higher when children are vaccinated at older ages. For example, anti-rotavirus IgA geometric mean titers for Vietnamese infants vaccinated against rotavirus at 9 and 13 wk were lower (77 U/ml) compared to infants vaccinated at 9 and 17 wk of life (176 U/ml) 
. Third, we assumed that some risk of intussusception exists following each of the first two doses of rotavirus vaccine in all countries worldwide; however, risk of intussusception has varied by setting, and robust studies in two large countries have not identified risk after dose 1 
. Fourth, even in our base scenario, we assumed high rates of intussusception case fatality in all WHO regions, about 2-fold higher than those reported in the literature.
On the other hand, the benefit-risk ratios might be inflated due to several factors. First, our base scenario assumes that the risk of intussusception relative to background does not increase with age. After the withdrawal of RotaShield, a debate persisted with regard to whether the RR of intussusception might have been higher for infants vaccinated beyond 14 wk of age 
. While limited data from an evaluation in Mexico does not suggest effect modification of risk by age for current vaccines 
, we incorporated a scenario of increased risk with age at vaccination that indicated that vaccination would avert 75 rotavirus deaths for each excess intussusception death. Second, our model might have overestimated vaccine coverage among children at the highest risk of dying from rotavirus as these might be the hardest to reach, thus inflating the mortality benefits of vaccination relative to the risks in our model. However, data from Mexico and Brazil, where substantial reductions in diarrhea deaths have occurred in all regions of both countries after the introduction of vaccine 
, provides some reassurance that vaccine is reaching those at the highest risk of dying.
While the numerical benefits of relaxing the age restriction on rotavirus vaccination exceed the risks, other factors are relevant for policy considerations. First, the age restrictions for rotavirus vaccines potentially offer an incentive to improve timeliness of vaccination, which would potentially have far reaching benefits beyond just prevention of rotavirus disease. However, reasons for delays in vaccination in developing countries are complex and it is not known if a policy of restricting the first dose of rotavirus vaccines alone would be a sufficient motivational factor for parents and countries to improve timeliness of vaccination. Indeed, some delays may be due to unavoidable factors, such as contraindications. Second, while the unrestricted vaccination scenario allows for vaccination at any age during the first 3 y of life, few children arrive for vaccination beyond 1 y of life. It is important to note that delays in vaccination particularly beyond 1 y of life will reduce benefits substantially because of increasing probability of acquiring natural immunity from wild-type rotavirus infection. Third, a death caused by an intervention may be perceived worse than a death caused by a failure to intervene 
. However, some evidence suggests that individuals may regret disease resulting from withholding vaccine as much as side effects from vaccination 
. Furthermore, after the RotaShield experience, ethicists argued equal culpability for deaths caused by withholding the vaccine as for deaths resulting from the vaccine 
. Finally, our analysis did not address high income countries where mortality from both rotavirus disease and from intussusception is uncommon, and thus the benefit-risk considerations will differ. Furthermore, vaccination is more timely in these settings (e.g., in the United States, 93% of the DTP1 is given by 15 wk of age 
), and thus decisions will likely have to be made at a country level based on evaluation of local data.
In summary, using emerging, real-world data on rotavirus and intussusception mortality and rotavirus vaccine efficacy, safety, and coverage, we estimate that removing the age restrictions on rotavirus vaccination would avert 47,200 additional rotavirus deaths in low- and middle-income countries. In April 2012, WHO's Strategic Advisory Group of Experts reviewed the evidence presented in this paper and recognized that the 15-wk and 32-wk age restrictions for rotavirus vaccines are preventing vaccination of many vulnerable children 
. SAGE encourages timely vaccination, but no longer universally recommends the age restrictions, supporting their removal in seetings where mortality benefits outweigh the risk so that many thousands more deaths would be averted and immunization programs are able to immunize children who are currently excluded from the benefits of rotavirus vaccines. Age restriction policies will ultimately be decided at country level, but this analysis has shown a clear case for a change in policy that will be particularly instrumental for saving lives in settings where mortality from rotavirus is high and delays in timing of vaccination are common.