1. Timing of influenza vaccine in the tropics: reflections on the impact of a decade of research
Good morning everyone. I am Wladimir Alonso, researcher at Fogarty International Center and during these next 10 minutes I will be talking to you about the “Timing of influenza vaccine in the tropics: reflections on the impact of a decade of research”
Wladimir J. Alonso
Research Fellow and contractor at
Fogarty International Center / NIH (US)

2. In April last year, the World Health Organization convened an international panel to discuss the Seasonal Influenza Vaccine Composition for Tropics and Subtropics.

3. “countries in the tropics and subtropics have been advised to decide on the vaccine formulation and vaccination timing based on local influenza epidemiology and virology surveillance”
In the report that came out of that meeting, they inform that those countries “ have been advised to decide on the vaccine formulation and vaccination timing based on local influenza epidemiology and virology surveillance
That seems obvious, but actually it is not how the vaccine recommendations in the tropics are decided. Countries, even in the tropics, vaccinate mostly based on the hemisphe they belong to, not on “local influenza epidemiology”
So, it was a victory of several years of reseach from many institutions, that convinced the WHO to acknowledge that a good fraction of the world population who receives the annual influenza vaccine is probably immunized poorly.

4. Collaborative Network
5/7/2018
Collaborative Network
Supports research, data collection and sharing, workshops and training activities.
Network of 350+ collaborators in >50 countries
>120 publications describing the global epidemiology and evolutionary dynamics of influenza viruses
Now that we commemorate one decade of the MISMS project, it seems to be a good occasion to recognize and celebrate the role that this project -and therefore Fogarty International Center- had in this process.
And it was indeed a pivotal one, as we will see 4 4 4 4

5. 2005
First reference to possible problems on the timing of flu vaccine recommendations in the tropics?
“Previous weeks of southern cold were not necessarily in the right timing of vaccination for the entire country”
da Cunha, Camacho et al 2005
Influenza vaccination in Brazil: rationale and caveats.
Revista de Saúde Pública 39:129-36
So what is the history?: before the MISMS project there were already good studies on the seasonality of influenza in the tropics.
But it seems that the earliest explicit mention to the problem that tropical regions might pose for influenza vaccine recommendations was in a paper in a little known Brazilian journal.
Da Cunha and collaborators warned that “Previous weeks of southern cold were not necessarily in the right timing of vaccination for the entire country” 5

6. But overly, the timing of influenza vaccination in the tropics, was a “no problem” despite that, as we can see in this image, equatorial countries show a messy picture regarding seasonality, as opposed to temperate countries where the seasonality is well defined – and therefore making easy planning the timing of annual vaccination is straightforward.
This is the data on influenza circulation that has been collected from more than one hundred countries and is trusted to the WHO program, flunet

7. Phase of the major peak (months of the year)
Latitudinal gradient of seasonality of influenza in the tropics:
Alonso et al 2007 Am J Epidemiol 5 -5
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Phase of the major peak (months of the year)
Latitude (degrees)
The first study showing a gradient of seasonality in the tropics was a result of the MISMS project.
We extracted the seasonality of pneumonia and influenza from all Brazilian states and, when plotted agains latitude, gave this intersting result. It shows that one country, if situated in the tropics, could possess very different influenza seasonalities and we discussed these findings rising concerns about the timing of the Southern Hemispheric Vaccination
This study is more commonly referred to as the "Brazilian traveling wave paper"
J F M A M J J A S O N D
Association between latitude and the timing of the peak
of pneumonia & influenza mortality, Brazil

8. Seasonality and burden analysis
EPIPOI
a user friendly and freely available analytical tool for extraction of temporal and spatial parameters from epidemiological time-series
Capacity building
Seasonality and burden analysis
To perform the analyses I just mentioned we developed a software that has been evolving since then, and which has been made freely available.
This is actually the program that we are going to use in the workshop to perform several spatial-temporal analyses with your data or with the examples we provide.
It is rewarding to see that epipoi has moved beyond the realm of influenza, and is being used to study other morbidities, causes of injuries and infections.
Virus circulation

9. Geoghegan et al 2014
Seasonal Drivers of the Epidemiology of Arthropod-Borne Viruses in Australia. PLoS Negl Trop Dis 8(11)
Like this one, which investigated the Seasonal Drivers of the Epidemiology of Vector-Borne Viruses in Australia.

10. Mello et al 2009
First quantification of how many influenza viruses in the epidemic period after vaccination are matched by each hemispheric recommendation
Proposal of the methodology
But back to influenza: a second breakthrough came when we analyzed viral circulation data at the strain level. And we did it specifically aiming to quantify how well the Southern Hemispheric vaccine that had been giving to Brazilians since 1999 performed against the hypothetical alternative scenario, in which us, Brazilians, would had received the Northern Hemispheric vaccine instead. 10

11. Virus detections are analyzed based on their temporal, spatial and inmunogetic features simultaneously:
Belém
São Paulo
This is methodology we deviced: a simple –but rigorous- plotting of each strain detection on a time line AND…
Mello et al (2010)

12. Use of Southern (Historic) and Northern (Hypothetical) recommendation
… AND THE northen (blue) and southern (red) vaccine scenarios with their 9 months assumed immunization
Mello et al 2009 The dilemma of influenza recommendations 12

13. Matches with Southern Hemisphere recommendations
And matches were counted
Here we see the times that the Southern Hemispheric vaccine got it right in matching with the circulating viruses. 11 matches
Mello et al 2009 The dilemma of influenza recommendations 13

14. Matches with Northern Hemisphere recommendations
And here the times that the hypothetical Southern hemispheric vaccine would have captured the same viruses.
The results were quite shocking, as we showed that, in fact, for a extensive region of Brazil, the Northern Hemispheric vaccine would have actually performed twice better than the current one.
Mello et al 2009 The dilemma of influenza recommendations

15. Waiboci et al Which influenza vaccine formulation should be used in Kenya? A comparison of influenza isolates from Kenya to vaccine strains, Vaccine 34(23):
We are happy to report that the analytical method proposed in this study is being used by other groups to study this question in other countries.
Here we can see, for instance, this recent Kenyan paper where they also found that the best recommendation for that country is the one designed for the opposite hemisphere from where Kenya is located.

16. 2015 A global map of hemispheric influenza vaccine recommendations based on local patterns of viral circulation Alonso et al., Scientific Reports 5
Unfortunately, public health institutions are frequently slow in adopting changes based on new findings, so –answering the title of this talk- the impact of those findings in terms of changes in policies is still meager. Therefore we still have work to do in this front. And to speed up this change in policy, we are now performing some analyses that will provide specific figures in terms of hospitalizations and deaths that are being caused by the sluggishness in adopting the evidence-based hemispheric influenza recommendation. With these figures in hand it will be probably difficult for policy makers to procrastinate further their decisions on this matter.
In this recent study, (and using the same methodology we applied in the “travelling wave paper”) but on the FluNet influenza data, we showed which hemispheric recommendation each country should adopt. Circles indicate the timing of the primary peak of influenza detection of each country (here are the months), against its latitude. Here is the equatorial line, and these are , with the timing of the southern and northen hemisphere vaccinations
As you can see, many countries that are situated in the Southern hemisphere (these ones here) should receive the northern hemispheric vaccination. And these nothern hemipheric countries should actually receive the sourthern hemisphere vaccine.

17. The first clinical trials in history
Alonso et al 2015 This year is the 600th anniversary of the first known experiments conducted on influenza
And
The first clinical trials in history
The first biological controlled experiments in history
Therefore we can conclude that the MISMS project and our collaborations with several researchers - who we met mainly in our workshops - did play a pivotal role in the ongoing process of chaging the WHO recommendations for tropical countries
Because I still have one minute, I would like to mention briefly an example of another branching of the MISMS efforts, the historical studies. We discovered that this exact year is the sixth century anniversary of the oldest experiments to investigate the proximate causes of respiratory infections in history. Those were experiments carried out by imperial doctors of the Ming dynasty, in China. They are also actually the oldest controlled clinical trials in history (in fact four centuries before James Lind's experiments on scurvy) and two handred and half years before the experiments that were until now, considered, the oldest controlled biological experiments (the ones of Francesco Redi in 1668 rejecting the spontaneous generation).

18. Thanks!