Vaccine. 2015 Aug 7;33(33):4146-54. doi: 10.1016/j.vaccine.2015.05.081.

Persistence and avidity maturation of antibodies to A(H1N1)pdm09 in healthcare workers following repeated annual vaccinations.

 

Eidem S1, Tete SM2, Jul-Larsen Å1, Hoschler K3, Montomoli E4, Brokstad KA5, Cox RJ6.
  • 1The Influenza Centre, Department of Clinical Science, University of Bergen, Bergen, Norway; K.G Jebsen Centre for Influenza Vaccines, Department of Clinical Science, University of Bergen, Bergen, Norway.
  • 2The Influenza Centre, Department of Clinical Science, University of Bergen, Bergen, Norway; K.G Jebsen Centre for Influenza Vaccines, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Research & Development, Haukeland University Hospital, Bergen, Norway.
  • 3Health Protection England, London, UK.
  • 4Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.
  • 5Broegelman Research Laboratory, Department of Clinical Sciences, University of Bergen, Bergen, Norway.
  • 6The Influenza Centre, Department of Clinical Science, University of Bergen, Bergen, Norway; K.G Jebsen Centre for Influenza Vaccines, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Research & Development, Haukeland University Hospital, Bergen, Norway. Electronic address: rebecca.cox@uib.no.

 

Abstract

Healthcare workers are at increased risk of influenza infection through direct patient care, particularly during the early stages of a pandemic. Although influenza vaccination is widely recommended in Healthcare workers, data on long-term immunogenicity of vaccination in healthcare workers are lacking. The present study was designed to assess the persistence of the humoral response after pandemic vaccination as well as the impact of repeated annual vaccination in healthcare workers (n=24). Pandemic influenza vaccination resulted in a significant increase in haemagglutination inhibition (HI) antibody titers with 93-100% of subjects achieving protective titers 21-days post each of the three annual vaccinations. Seroprotective antibodies measured by HI, microneutralization and single radial hemolysis assays were present in 77-94% of healthcare workers 6 months post-vaccination. Repeated vaccination resulted in an increased duration of seroprotective antibodies with seroprotective titers increasing from 35-62% 12 months after 2009 pandemic vaccination to 50-75% 12 months after 2010 vaccination. Furthermore, repeated annual vaccination augmented the avidity of influenza-specific IgG antibodies. In conclusion, we have shown that A(H1N1)pdm09 vaccination induces high seroprotective titers that persist for at least 6 months. We demonstrate that repeated vaccination is beneficial to healthcare workers and results in further avidity maturation of vaccine-induced antibodies.

KEYWORDS: Avidity; Healthcare workers; Influenza; Long-term antibody persistence; Repeated vaccination

PMID: 26057137

 

Supplement

Influenza viruses infect the human population globally with an annual attack rate estimated at 5%–10% in adults and 20%–30% in children. These annual outbreaks result in considerable morbidity and mortality, with an annual estimate of 3 to 5 million cases of severe illness and 250 000- 500 000 deaths worldwide. The most affected groups are the young, elderly and chronically ill (1). These risk groups are recommended for annual influenza vaccination, as vaccination is the most effective method to prevent infection.

The outbreak of the novel H1N1 influenza A virus in 2009 (A(H1N1)pdm09), antigenically distinct from the recently circulating pre-pandemic seasonal H1N1 viruses, posed a serious risk to global human health (2). The outbreak first emerged in Mexico and California and then continued to spread globally, generally causing mild infection, although severe illness and fatalities were reported(3). An estimated 1 million people in Norway were infected by the A(H1N1)pdm09 virus in 2009(4). Healthcare workers and individuals in high risk groups were initially prioritized for vaccination and 2.2 million people (45 % of the population) were vaccinated in Norway during the pandemic(5). In 2010, the World Health Organization declared the A(H1N1)pdm09 virus to have entered a post-pandemic period and the virus continued circulating as a seasonal virus. Consequently, seasonal trivalent influenza (TIV) vaccines from 2010 include the A(H1N1)pdm09 virus as the H1N1 strain(6).

Questions have been raised regarding the relevance of repeated influenza vaccination. There have been occasional reports of lower immunogenicity of seasonal influenza vaccines in adults who have been previously vaccinated with seasonal influenza vaccines (7, 8). Other studies reported similar or better effectiveness of influenza vaccination in previously vaccinated individuals (9, 10). Furthermore, higher antibodies were reported pre-vaccination in previously vaccinated individuals compared to those individuals with no previous vaccination(10, 11). We therefore conducted this clinical study to evaluate the vaccine immunogenicity as well as the antibody persistence in healthcare workers as they were prioritized for vaccination in Norway during the 2009 pandemic and are recommended for annual influenza vaccination.

Antibodies are currently the acceptable correlate of immune protection against influenza and are measured by hemagglutination inhibition (HI) assay and microneutralization assay. Pre-vaccination, protective HI antibody titers were observed in a fraction of the healthcare workers. This could be attributed to pre-existing antibodies as a result of previous or recent subclinical infection with the pandemic H1N1 virus. Vaccination induces seroprotective antibodies. Importantly, these protective antibodies persisted for at least 6 moths in the majority of the healthcare workers. Vaccination in 2010 and 2011 with seasonal influenza vaccines that contained the same pandemic H1N1 virus boosted their antibody responses. We measured the antibody responses using 3 separate serological assays and showed that the antibodies increased and were sustained for at least 6 months following each vaccination in most subjects. The paper featured at this site describes this study(12).

We measured the strength of binding between the antibodies and virus antigen, Hemagglutinin, in an avidity assay in order to assess the antibody maturation with repeated seasonal vaccination. We showed that repeated vaccination with vaccines containing the same pandemic H1N1 virus antigen increased the avidity of the antibodies. The avidity of the antibodies gradually increased with the highest avidity being observed after the third vaccination(12). The increase in antibody avidity seen with subsequent annual vaccination could be due to the recall of long-term memory B cells that were generated at previous exposure or vaccination, which undergo further maturation and differentiation resulting in generation of antibodies with increasing avidity (13). This increase in avidity is related to the successful priming of immunological memory that will respond quickly when re-exposed to the same virus.

As pandemic vaccination and subsequent seasonal vaccination resulted in high seroprotective antibodies that show long term persistence and increased avidity, promoting enthusiasm for annual influenza vaccination should be encouraged. Mandatory vaccination policies as well as improved vaccine access increase vaccine uptake in HCWs (14, 15). Vaccination of healthcare workers against influenza reduces absenteeism and the transmission to vulnerable patients as well as to collegues thereby maintaining the integrity of the healthcare system. Vaccinated and protected healthcare workers are more likely to advice and explain the benefits of vaccination to patients.

 

References

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