Monday, July 28, 2014

BMC: Decline Of Antibody Titers With A(H1N1)pdm Over Time


Credit NIAID



# 8875


The arrival of a novel H1N1 influenza pandemic virus in 2009 – the first one in more than 40 years – has provided researchers with unique opportunities to observe how a newly introduced flu virus behaves in humans, and quite frankly, in other species as well (see The 2009 H1N1 Virus Expands Its Host Range (Again)).


Serological studies that would have been impractical before on H3N2 or the old seasonal H1N1 virus – due to decades of ongoing exposure to these strains – suddenly became possible with a new flu in town.


One of the unanswered questions surrounding our immune response to influenza infection is how long does our acquired immunity last?  


Admittedly, the answer to that question will vary from one person to the next, and depend on a variety of factors including the strain of flu, the person’s age, general health, and state of their immune system.  And there seems to be a difference between the duration of immunity gained from actual infection vs. through vaccination.


Despite circulating now for more than 5 years, the (now seasonal) H1N1 virus remains antigenically very similar to the pandemic strain that emerged in the spring of 2009.  So much so that an an A/California/7/2009 (H1N1)pdm09-like virus will be used for the sixth year running in the flu vaccine. 

Yet, despite having a half of decade of vaccination and natural exposure to this new H1N1 virus, last year saw a particularly heavy H1N1 flu season in North America. Normally, we’d look to antigenic drift to explain a major resurgence of a seasonal flu virus after several years, but H1N1 has been remarkably (albeit, not totally) stable in that regard.


Drift is the standard evolutionary path of influenza viruses, and comes about due to replication errors that are common with single-strand RNA viruses (see NIAID Video: Antigenic Drift) Drift is primarily responsible for the need to change flu vaccine strains every couple of years (something that is yet to happen with H1N1).


Another possibility is waning immunity, something that is recognized (particularly with vaccines, and among the elderly), but has been difficult to quantify in the past.  Given the immune system’s tabula rasa with regards to the 2009 H1N1 virus, it has become possible to track the decline of antibody titers of a cohort of individuals who were first exposed five years ago.


Rate of decline of antibody titers to pandemic influenza A (H1N1-2009) by hemagglutination inhibition and virus microneutralization assays in a cohort of seroconverting adults in Singapore

Jung Pu Hsu, Xiahong Zhao, Mark I-Cheng, Alex R Cook, Vernon Lee, Wei Yen Lim, Linda Tan, Ian G Barr, Lili Jiang, Chyi Lin Tan, Meng Chee Phoon, Lin Cui, Raymond Lin, Yee Sin Leo and Vincent T Chow

BMC Infectious Diseases 2014, 14:414  doi:10.1186/1471-2334-14-414

Published: 28 July 2014

Abstract (provisional)


The rate of decline of antibody titers to influenza following infection can affect results of serological surveys, and may explain re-infection and recurrent epidemics by the same strain.


We followed up a cohort who seroconverted on hemagglutination inhibition (HI) antibody titers (>=4-fold increase) to pandemic influenza A(H1N1)pdm09 during a seroincidence study in 2009. Along with the pre-epidemic sample, and the sample from 2009 with the highest HI titer between August and October 2009 (A), two additional blood samples obtained in April 2010 and September 2010 (B and C) were assayed for antibodies to A(H1N1)pdm09 by both HI and virus microneutralization (MN) assays. We analyzed pair-wise mean-fold change in titers and the proportion with HI titers >= 40 and MN >= 160 (which correlated with a HI titer of 40 in our assays) at the 3 time-points following seroconversion.


A total of 67 participants contributed 3 samples each. From the highest HI titer in 2009 to the last sample in 2010, 2 participants showed increase in titers (by HI and MN), while 63 (94%) and 49 (73%) had reduction in HI and MN titers, respectively.

Titers by both assays decreased significantly; while 70.8% and 72.3% of subjects had titers of >= 40 and >= 160 by HI and MN in 2009, these percentages decreased to 13.9% and 36.9% by September 2010. In 6 participants aged 55 years and older, the decrease was significantly greater than in those aged below 55, so that none of the elderly had HI titers >= 40 nor MN titers >= 160 by the final sample.

Due to this decline in titers, only 23 (35%) of the 65 participants who seroconverted on HI in sample A were found to seroconvert between the pre-epidemic sample and sample C, compared to 53 (90%) of the 59 who seroconverted on MN on Sample A.


We observed marked reduction in titers 1 year after seroconversion by HI, and to a lesser extent by MN. Our findings have implications for re-infections, recurrent epidemics, vaccination strategies, and for cohort studies measuring infection rates by seroconversion.

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.


The entire study is available, and well worth reading, but I’ve excerpted two paragraphs below that sum up their findings.  


The objective of our study was to understand temporal changes in antibody titers following seroconversion during the initial epidemic of A(H1N1)pdm09 infections in  Singapore. Our results revealed a fairly rapid decline in antibody titers following seroconversion, with only a fifth of those who originally had HI titers of  ≥40 and half of those with MN titers of  ≥160 still  having  titers  above  the  respective  cut-off  points  after  a  year.  There  was  also  some indication  that  the  rate  of  decline  was  higher  in  older  individuals,  and  that  the  change  in antibody  titers  measured  by  HI  was  greater  than  by  MN.  Symptomatic  infections  were associated with higher starting antibody titers, and continued to have marginally higher titers in subsequent samples, at least by MN assays.



Six  months  and  one  year  after  antibodies  peaked  following  presumptive  infection  with A(H1N1)pdm09, only 25% and 14% of participants respectively had antibody  titers against A(H1N1)pdm09 that would be considered protective (HI titer ≥40). The decline in antibody titers may explain susceptibility to re-infections, and recurrent epidemics following the initial epidemic of infections during the pandemic. It also suggests that influenza vaccination may have to be administered more frequently in the tropics where there is year-round circulation of influenza viruses. The rate of decline in elderly individuals may be even more rapid, and if our  findings  are  confirmed,  may  necessitate  alternative  strategies  of  influenza  vaccine development for this vulnerable group.



A pretty good reminder that even if you got the vaccine last year – or worse, endured the flu last winter – you may not be carrying sufficient immunity forward into the new flu season to protect you against re-infection. 


And given that H3N2, and two lineages of Influenza B, are also in circulation – your risks of catching some kind of flu are compounded further.


Which is why, even though the H1N1 component of the flu vaccine remains unchanged this year, it is a good idea to get the flu vaccine every year.  


Despite variable and sometimes disappointing VE (Vaccine Effectiveness) numbers (see CIDRAP: A Comprehensive Flu Vaccine Effectiveness Meta-Analysis) - particularly among the elderly (see BMC Infectious Diseases: Waning Flu Vaccine Protection In the Elderly) - we continue to see evidence of substantial benefit from the flu shot.


For more, you may wish to revisit:


CDC: Flu Shots Reduce Hospitalizations In The Elderly
Research: Low Vaccination Rates Among 2013-2014 ICU Flu Admissions
Two Studies On The 2009 Pandemic Flu Vaccine & Pregnancy

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