We have characterized the epidemiology of a recrudescent 4th
wave of A/H1N1 influenza transmission in Mexico spanning 01-December 2011 to 10-Feberuary 2012, based hospitalizations for acute respiratory infections and laboratory-confirmed A/H1N1 infections. We compared the impact, severity, age patterns, and reproduction number of this 4th wave with those of earlier pandemic waves in spring, summer and fall 2009 in Mexico, ,
. We used individual-level patient information collected through a prospective influenza surveillance system put in place especially for the 2009 pandemic by the largest Mexican Social Security medical system and providing daily data during 2009-2012 
. Our data show that the nationwide peak level of daily ARI hospitalizations obtained so far in early 2012 (it may not yet have peaked) has already exceeded the peak of ARI hospitalizations observed during the major fall pandemic wave in 2009. We have also documented a significant increase in the proportion of A/H1N1 hospitalizations and deaths among persons >=60 y, relative to the 2009 pandemic, and a significant reduction in the proportion of A/H1N1 hospitalizations and deaths among school age children.
The observed change in age distribution of hospitalization and deaths in the post 2009 pandemic period is reminiscent of the influenza seasons following the 1918 influenza pandemic ,,
and the 1968 pandemic 
. A quantitative analysis of excess mortality prior to and after the1918 influenza pandemic found that the age distribution of influenza-related mortality returned to pre-pandemic mortality levels a few years after the initial pandemic waves as a result of emerging drift variants ,
. Hence the age shift seen in the 2011-12 winter season could signal either a gradual emergence of drift A/H1N1 variants, and/or a build up of immunity among younger populations. Both have implications for influenza prevention and mitigation strategies, which we discuss below.
During the first year of circulation of the 2009 A/H1N1 influenza pandemic virus, protection from influenza-related morbidity and mortality rates was reported in people over 60 years. This phenomenon of “senior sparing” in age cohorts born prior to the 1957 pandemic is consistent with first exposure to antigenically-related A/H1N1 viruses in childhood, a pattern consistent with the antigen recycling and original antigenic sin hypotheses ,,,,
. A high fraction of the Mexican population is now protected against the 2009 A/H1N1 influenza virus through natural exposure in 2009 (children and young adults) or prior immunity (seniors) 
and by pandemic vaccines. Over 7 million of seasonal influenza vaccine (featuring a good match for the H1N1-pdm vaccine component) were administered in 2011-12 winter (35% vaccination coverage among IMSS-affiliated seniors >=60 years; 70% among <5 years; 40% among 50-59 years; and 24% among 5-9 years).
Although we saw evidence of a shift in the age distribution of 2011-12 cases towards seniors, the absolute risk of getting hospitalized was still relatively low in this age group, relative to those in younger adults. The declining rates of severe cases in younger age groups is most consistent with build-up of immunity. Overall the age distribution of recent A/H1N1 influenza hospitalizations and deaths in Mexico is relatively flat and not quite back to the normal “J-shaped” age risk profile that characterizes seasonal influenza. In the long run, we expect the pandemic A/H1N1 virus to drift genetically to escape mounting population immunity – perhaps with the result that seniors are no longer protected 
. Hence the epidemiological evidence is consistent with the genetic and antigenic information published on circulating influenza virus, suggesting a lack antigenic drift in A/H1N1 viruses in Mexico or elsewhere in winter 2011-12, a season associated with relatively low A/H1N1 activity globally 
Since transmission of the A/H1N1 influenza virus was sporadic in the winter of 2010-2011 in Mexico, we cannot rule out the possibility of some loss of population immunity since 2009. We estimated a reproduction number for the ongoing A/H1N1 epidemic to be significantly lower to that of the spring (R~1.8-2.1) and summer (R~1.6-1.9) pandemic waves in 2009 in Mexico, but in close agreement with estimates of the fall (3rd) 2009 wave (R~ 1.2-1.3)
Perhaps the most surprising finding of this analysis is the occurrence of a substantial 4th
wave of pandemic A/H1N1 activity in Mexico, a country which has already experienced severe excess mortality impact during 3 waves of transmission in 2009 ,
. Although we are just beginning to assess the global mortality burden of the 2009 A/H1N1 virus in the pandemic and post-pandemic period, important geographical variations in the number, timing, transmissibility and impact of sequential pandemic waves are obvious. For instance, the UK experienced 2 waves in spring and fall 2009, to be followed by a relatively severe recrudescent wave in 2010-11, not seen in other European countries 
. The US experienced the brunt of the pandemic burden in the first year of A/H1N1 circulation. To our knowledge, the 4-
wave pattern seen in Mexico in 2009-12 has not been reported in other countries. Whether these differences can be explained by geographical variation in prior immunity, seasonal drivers, control strategies, connectivity, health and healthcare, is unclear and remains a key area for future research.
In summary our findings indicate a changing age distribution of laboratory-confirmed A/H1N1 influenza hospitalizations and deaths in winter 2011-12, relative to 2009-10 A/H1N1 pandemic patterns. The proportion of hospitalizations and deaths is increasing in seniors >=60 years, an age group that was largely protected during the early pandemic waves in 2009. In contrast, rates of A/H1N1 hospitalizations and deaths are declining among younger population groups, consistent with a gradual build up of immunity. This gradual change in the age distribution A/H1N1 influenza in 2011-12 in Mexico is reminiscent of post-pandemic patterns in past influenza pandemic. As the 4th
wave is still ongoing, it is too early to determine whether it is more severe than the previous waves in terms of mortality – something that occurred in the 1889 pandemic in which a 3rd
wave occurring in the winter of 1891-92 was far more deadly than previous waves ,
Whether other countries will eventually experience similar severe recrudescent waves of A/H1N1 activity remains to be seen. A multinational comparison of the epidemiology of pandemic and post-pandemic waves would be useful to shed light on the long-term transmission dynamics and build up of immunity to pandemic viruses, and inform control strategies.