Dear Dirctor of CCID,

I sent you the first version of this hypothesis on 31 of August 2009 but I didn’t get any response. I suspected that your secretary might discard my hypothesis and it wouldn’t reach you since Reference 1 is a little too difficult for ordinary intelligent people to understand and if you cannot understand Reference 1, you cannot evaluate my hypothesis. So I rewrote my hypothesis so that you can evaluate my hypothesis without reading Reference 1.
Sincerely,
Shoichi Watanabe

The selection pressure of the hierarchy of murine immunity to the influenza A virus made the second wave of the "Spanish" influenza virulent (Revised)

Preface
I sent the first version of this hypothesis to Dr Margaret Chan of WHO on 31 of August 2009.
Then I found some intelligent people had difficulty in understanding Reference 1, “1918 Influenza: the Mother of All Pandemics”, written by Dr Jeffery K. Taubenberger who was the first to sequence the genome of the influenza virus, which caused the 1918 pandemic of “Spanish flu”, since he used technical terms which ordinary intelligent people don’t know. I suspected that Dr Margaret Chan’s secretary might discard my hypothesis and it wouldn’t reach Dr Margaret Chan since if you cannot understand Reference 1, you cannot evaluate my hypothesis. And I sent my hypothesis to about 200 influential institutes on influenza in the world. I thought one of them would ask Dr Margaret Chan about my hypothesis at least.
I waited for 3 weeks but I didn’t get any response. I happened to know experts check contributed theses at Nature and I contributed my hypothesis to Nature. I got an email the next day which said “we cannot offer to consider it for publication in Nature” but they offered to transfer my hypothesis to another Nature journal. And it was transferred to Nature Immunology.
The next day I got an email from Dr Jamie D.K. Wilson, it said “Nature Immunology does not publish short hypothesis-based articles” and it also indicated my hypothesis didn’t have novelty. Since my hypothesis is apparently novel, it meant my hypothesis didn’t have novel supporting data. He too offered to transfer my hypothesis to another minor journal but I didn’t respond to him since I thought decisions to publish my hypothesis in a minor journal wouldn’t help stop virulent second waves.
The next day I got an email from Genes and Immunity which said “Based on our experience of the fate of similar manuscripts it is the Editors' opinion that your paper will not receive sufficient priority for publication in Genes and Immunity. Therefore, we have decided to inform you that it would be in your best interest to submit it elsewhere.” But I didn’t know about transferring my hypothesis to Genes and Immunity. Some one transferred it to Genes and Immunity.
I suppose they couldn’t deny my hypothesis and they also knew its importance but they have guidelines on supporting data to publish theses in Nature journals, and all they could do was to offer to transfer it to another journal in spite of knowing the guideline.
I believe that if there is a person who can take action to prevent virulent second waves based on my hypothesis, it would be Dr Margaret Chan who brought the 1997 H5N1 avian influenza outbreak under control by the slaughter of 1.5 million chickens in Hong Kong.
I suppose if ordinary people can evaluate my hypothesis without reading Reference 1, there would be a possibility that my hypothesis reaches Dr Margaret Chan. So I am going to show the validity of my hypothesis by answering 8 unanswered questions on "Spanish" flu.
"Spanish flu" has been researched for more than 90 years, and the influenza virus recovered from lung tissue of a 1918 flu victim whose body had remained frozen in the permafrost of Alaska was sequenced completely in 2005. But some questions on “Spanish” flu are still unanswered. I would like to show that they can be answered based on my hypothesis and that it is a clue to preventing virulent second waves.

8 unanswered questions (These questions will be answered after the hypothesis)
1. Where did the 1918 virus come from?
(1) At the amino acid level, 3 strains of Influenza virus gene sequences, ones from wild birds collected before the 1918 flu pandemic, ones from a 1918 flu victim and ones from wild birds isolated today, show little difference.
(2) At the nucleotide level, 2 strains of Influenza virus gene sequences, ones from wild birds collected before the 1918 flu pandemic and ones from wild birds isolated today, show little difference but influenza virus gene sequences from a 1918 flu victim are quite different.
(3) The 1918 influenza spread among humans and swine simultaneously.
These 3 facts indicate the 1918 virus didn’t come from wild birds or swine. It came from unknown source.
2. Why was the virus so infectious?
3. Why was it so fatal?
4. Why did it kill so many healthy young adults?
5. Why 3 waves occurred in a short period?
6. Why did the second wave cause simultaneous outbreaks in the Northern and Southern Hemispheres from September to November?
7. Why did influenza epidemics settle into annual epidemic recurrences and lower death rates within a few years after 1918?
8. Could a 1918-like pandemic appear again?

Preface for the first version
This is an attempt to explain the virulence of the "Spanish" influenza pandemic of 1918-1919 with the concept of “hierarchy of immunity.“ The hypothesis indicates that the 2009 influenza pandemic will have virulent second waves. But we might be able to stop them by controlling mice and cats.

Hypothesis
1. A population is graded according to strength of immunity to a novel influenza A virus. In this hierarchy of immunity, those who will not be infected with the virus belong to the uppermost level and those who can be infected with the virus without mutation belong to the lowest level.
2. When the virus spreads, it mutates continually by the selection pressure of the hierarchy of immunity and it spreads from a lower level to the next upper level when it becomes more infectious.
The number of the people who can be infected is as follows.
N = N1 - N1i + N2 - N2i + … + Nx - Nxi
N : the number of people who can be infected
N1 : the number of people who belong to the lowest level
N1i : the number of people who are infected in the lowest level
N2 : the number of people who belong to the 2nd lowest level
N2i : the number of people who are infected in the 2nd lowest level
Nx : the number of people who belong to the xth lowest level
Nxi : the number of people who are infected in the xth lowest level
When the virus continues spreading, the number of people who can be infected(N) continues increasing and the virus becomes more and more infectious. Then it begins to spread explosively and the number of people who can be infected (N) decreases rapidly. When most of the infected people recover, new patients of the influenza are seldom seen. This is the end of the first wave.
3. The influenza A virus infects a host in two main ways on mutation, large-droplet infection to the upper respiratory tract and small-particle aerosol infection to lung tissue.
In the first wave, the virus spreads mainly with large-droplet infection and large-droplet infection suppresses small-particle aerosol infection.
4. When the virus spreads explosively at the end of the first wave, both large-droplet infection and small-particle aerosol infection become the most infectious and some healthy young adults may have pneumonia but large-droplet infection still suppresses small-particle aerosol infection.
5. When the virus spreads explosively around the end of the first wave, small-particle aerosol infection becomes infectious enough for the virus to spread to mice.
6. The virus infects lung tissue of mice mainly with small-particle aerosol, and the selection pressure of the hierarchy of murine immunity promotes mutation on small-particle aerosol infection.
7. The number of mice that can be infected increases and the virus spreads explosively after a few months. Then the virus spreads in humans again. This is the beginning of the second wave.
8. In the second wave, small-particle aerosol infection, which is apt to cause pneumonia, is predominant to large-droplet infection. This is why the second wave is virulent.

An infection route from mice to humans
It wouldn't be difficult for researchers to find mice infected with 2009 influenza (H1N1) virus but it would be difficult to find an infection route from mice to humans. All I can think of is that cats that eat an infected mouse transmit the virus to humans. We might be able to stop the second wave by controlling mice and cats.

The 8 Questions - and the Answers
1. Where did the 1918 virus come from?
Answer: The virus which caused second waves came from mice. The virus which caused the first wave hasn’t been found, but the fact that influenza virus gene sequences from wild birds collected before the 1918 flu pandemic show little difference at the amino acid level from ones from a 1918 flu victim indicates that the virus which caused the first wave came from wild birds.
2. Why was the virus so infectious?
Answer: When the virus spread explosively at the end of the first wave, small-particle aerosol infection became infectious enough for the virus to spread to mice, and when it spread in mice with small-particle aerosol infection, the selection pressure of the hierarchy of murine immunity promoted mutation on small-particle aerosol infection. When it spread in humans again via cats, small-particle aerosol infection became dominant.
Small-particle aerosol infection to lung tissue was much more infectious than large-droplet infection to the upper respiratory tract once it became dominant since aerosols stayed longer in the air than large droplets and they infected much more people in closed space than large droplets..
3. Why was it so fatal?
Answer: Second waves spread with small-particle aerosol infection to lung tissue and small-particle aerosol infection to lung tissue caused acute pneumonia.
4. Why did it kill so many healthy young adults?
Answer: A graph of the mortality rate by age group shows W-shaped curve since
(1) many young adults had naturally acquired immunity to the novel influenza virus on large-droplet infection to the upper respiratory tract and they were not infected when the first wave came,
(2) as a result, their immunity was not strong enough to avoid small-particle aerosol infection to lung tissue when the second wave came and many of them died.
(3)naturally acquired immunity to the novel influenza virus on large-droplet infection to the upper respiratory tract becomes stronger with age but it becomes weaker with age after about 30 years old.
5. Why 3 waves occurred in a short period?
Answer: There were 2 cases;
(1) In Hachioji of Tokyo (population: 540,000), where I live, the first wave of 2009 influenza (H1N1) came twice, at the beginning of July and at the end of August after many people traveled in summer vacation. This indicates the virus became more infectious by the hierarchy of human immunity in about 2 months and when some travelers brought it to Hachioji at the end of August it could spread again.
The same phenomenon occurred with second waves of “Spanish” flu but they were recognized as different waves since many people died in each wave.
(2) Different people were infected with a different virus from different mice at the beginning of second waves.
6. Why did the second wave cause simultaneous outbreaks in the Northern and Southern Hemispheres from September to November?
Answer: When the virus spread explosively around the end of the first wave, small-particle aerosol infection became infectious enough for the virus to spread to mice.
The virus infects lung tissue of mice mainly with small-particle aerosol, and the selection pressure of the hierarchy of murine immunity promoted mutation on small-particle aerosol infection.
The number of mice that could be infected increased and the virus spread explosively after a few months. Then the virus spread in humans again via mice. This was the beginning of the second wave.
When mice infected with the virus were brought from one country to another around the end of the first wave, the virus would spread explosively in both countries almost at the same time since the virus could infect mice which belonged to the same level of the hierarchy of murine immunity. For example, when the virus spread up to the 10th lowest level of the hierarchy of murine immunity in U.S.A. and mice infected with the virus were brought to France, mice which belonged to the same levels, from the 1st to 10th lowest level, could be infected with the virus. So the infection might reach a certain level almost at the same time and the virus spread explosively in both countries almost at the same time. Then the virus spread in humans again via mice. This was the beginning of the second wave in both countries.
7. Why did influenza epidemics settle into annual epidemic recurrences and lower death rates within a few years after 1918?
Answer: When 2 types of influenza virus of the same strain, one with weak symptoms and one with strong symptoms, were spreading in humans, one with weak symptoms became dominant and one with strong symptoms disappeared in the long run. Because when symptoms were strong, people were apt to stay home and it helped to stop the virus spreading and when symptoms were weak, people did’t stop daily activities and it helped the virus spread.
8. Could a 1918-like Pandemic Appear Again?
Answer: Yes. Virulent second waves of 2009 influenza (H1N1) may come in the middle of November at the earliest.

References
1. Jeffery K. Taubenberger*Comments and David M. Morens: 1918 Influenza: the Mother of All Pandemics
2. World Health Organization (WHO) Writing Group: Nonpharmaceutical Interventions for Pandemic Influenza: Transmission Characteristics of Influenza Viruses