Difference in Global Mortality in the Influenza Pandemic of 1968-1969

This week in IMMU 7630, we’ll be talking about flu pandemics. To preview/review, influenza viral particles have surface proteins called neuraminidases and hemagglutinins. There are 9 known neuraminidases (called N1, N2, etc.) and 16 known hemagglutinins (H1, H2, etc.). Viruses are named for the neuraminidases and hemagglutinins on their surface (H1N1, H3N2, H5N1, etc.). Pandemics occur when a known flu virus, such as the H1N1 virus, reasserts with an unknown flu virus (often a wild bird flu), such as H2N2. The new virus is an H2N2 and not related to the H1N1 strain. Humans have no pre-existing immunity to this new virus, and this can cause a pandemic or epidemic.

One example of this was the 1957/58 Asian flu virus which originated in China. It occurred when 3 genes from wild duck flu virus reasserted with five genes for circulating human strain (it was an H2N2 viruThe death rate was highest in the elderly (those 65 or older).

In 1968/69, there was a new pandemic, caused by the “Hong Kong Flu”. It was an H3N2, occurring when two genes from a wild duck flu virus reasserted with the six genes from the circulating H2N2 virus. Although there were ~1-4 million deaths worldwide, there were substantially less deaths in the US than in 1957/58 pandemic (~34,000).

The impact of this pandemic in different countries, by different age groups was looked at by C. Viboud et al (http://www.journals.uchicago.edu/doi/pdf/10.1086/431150?cookieSet=1). This pandemic had two seasons – 1969/68 and 1969/70. Interestingly, the mortality rates by country differed for these two seasons. The authors examined excess deaths from influenza and also looked at the proportion of excess pneumonia and influenza mortality (P&I mortality) in The United States, Canada, Japan, England, Australia, and France.

For each country, the authors examined the proportion of excess pneumonia and influenza mortality (P&I mortality) in persons <65 years of age. They found that this P&I mortality increased 2.2-4.6 fold during the first H3N2 pandemic season, as compared to the last H2N2 season. This “age-shift” is often characteristic of pandemics, indicating that a new virus form is circulating that a large proportion of the population has not been exposed to.

It has actually been speculated that during the 1968/69 pandemic, older people might have actually had some pre-existing immunity to the H3N2 virus from the 1957/58 virus. There was only a shift in the hemagglutinin; the neuraminidase remained the same. Many people might have had antibodies and memory T-cells to the H2N2, and they might have cross-reacted with the H3N2 virus. Unfortunately, this paper did not look at smaller age groups to try to discern this.

The remainder of the paper was spent focusing on the geographic differences in the pandemic. In the United States and Canada, the majority of the excess deaths from influenza occurred in the first year of the pandemic (70% and 54%, respectively), while in Japan, England, Australia, and France, the percentage of total excess deaths in the first year were much smaller (32%, 23%, 22%, and 15% respectively). The pandemic seemed to affect the North American continent quickly in the first year, while Europe, Asia, and Australia had more deaths from the flu the second year. This phenomenon is referred to as a “smoldering” pandemic.

This difference in pandemic is probably caused because in North America and Canada, people had very little pre-existing immunity to either the neuraminidase or hemagglutinin gene; thus, many of them got sick the first year. In contrast, people in Europe, Asia, and Australia would have had high pre-existing immunity. Phylogenetic analyses of the neuraminidase gene did show that there was genetic drift during this time period; that is, there are two genetically distinct gene clusters for the N2 gene, one in 1968/69 and the other in 69/70.

This led the authors to hypothesize that people in Europe, Asia, and Australia had high exposure to the H2N2 virus during its last pandemic season, and that the emergent H3N2 virus was fairly similar to the H2N2 virus. In contrast, people in North America did have as much exposure to the late H2N2 virus and thus less pre-existing immunity to the new H3N2 virus.

The severe second pandemic season in Europe, Asia, and Australia was still puzzling. To analyze this, the authors looked at phylogenetic relationships of the hemagglutinin H3 gene and the neuraminidase N2 gene. For the neuraminidase N2 gene, they found two distinct gene clusters, with different antigenic sites. The first cluster was present in the first pandemic season 1968/69, while the second, with a new antigenic site, was found in 1969/70. This genetic drift might explain why the pandemic was more severe in Europe, Asia, and Australia the second season. People now needed to make new antibodies to the new antigen. Interestingly, since the hemagglutinin gene did not drift much during this time, a substantial proportion of the North American population would have already made antibodies to it and would still be protected.

The “smoldering” response suggests that if a vaccine could have been made after year 1 in Europe, Asia, and Australia, a good percentage of the deaths could have been prevented. This is an interesting idea, although it unfortunately does not help us to predict new future pandemics.

After thinking about this paper and what we have learned in class, I was trying to think about how vaccine repsonses to infectious agents like influenza might be improved on a yearly basis. In the case of the 1968/1969 pandemic, the mortality varied around the world because the virus drifted differently. There have also been instances in the United States where the yearly vaccine is very different than that year's virus and is thus ineffective. Do we need to have a more global effort when it comes to vaccine production? Or, each year, do we need to make a vaccine that is a combination of vaccines in order to catch more variation in virus? Obviously, both of the ideas might be complicated and cost-prohibitive. It would be hard to justify either during non-pandemic years.