A number of epidemiological and serological studies indicate that trivalent influenza seasonal vaccination is unlikely to confer any protection against pandemic influenza (H1N1) 2009 infection

Description:
Hancock K, Veguilla V, Lu X, et al. Cross-reactive antibody responses to the 2009 pandemic H1N1 influenza virus. N Engl J Med 2009 Nov 12;361(20):1945-52.

Most of the epidemiological data available so far show that nearly 80% of all pandemic influenza (H1N1) 2009 cases are individuals under 30 years of age and there have been relatively few cases in individuals 65 years and older [1,2]. This observation suggests that older people might be less affected due to some enduring immunological memory of an earlier influenza A(H1N1) infection with a similar phenotype. Hancock et al.’s study verifies this thesis through a serological study conducted in the US that found that only 4% (4 of 107) persons who were born after 1980 had natural pre-existing cross-reactive antibody titres of 40 or more against H1N1 2009. The proportion of individuals with pre-existing cross-reactive antibodies increased with age and was 34% (39 of 115) in those born before 1950 (titres of 80 or more) and 100% in 11 individuals who were born between 1910 and 1929. The study also provides evidence to answer the question on whether vaccination with 2008/2009 or previous seasonal vaccines has any protective effect against the pandemic influenza (H1N1) 2009 infection. According to Hancock’s study, vaccination with seasonal trivalent inactivated influenza vaccines resulted in an increase in the level of cross-reactive antibody to H1N1 2009 by a factor of four or more in none of 55 children between the ages of six months and nine years; in 12 to 22% of 231 adults between the ages of 18 and 64 years; and in 5% or less of 113 adults 60 years of age or older. Seasonal vaccines that were formulated with adjuvant did not further enhance cross-reactive antibody responses. However, vaccination with the A/New Jersey/1976 swine influenza vaccine substantially boosted cross-reactive antibodies to H1N1 2009 in adults [3].

ECDC comment (30 November 2009)
This study shows that vaccination with recent seasonal influenza vaccines, even when formulated with adjuvants, provides hardly any protection against pandemic influenza (H1N1) 2009. This is due to the genetic and antigenic differences between the seasonal influenza A(H1N1) virus included in the 2008/2009 and other recent seasonal vaccines and the pandemic A(H1N1)v virus. This lack of protection confirms the results of an earlier seroepidemiological study conducted in the US where prior vaccination with seasonal vaccines did not result in a significant increase of cross-reactive antibody response to the pandemic virus [4].

Assessing whether seasonal influenza vaccines confer any protection against pandemic (H1N1) 2009 has currently limited public health relevance. Effective strain-specific pandemic vaccines are available and are being administered in most countries. In addition most of the Northern Hemisphere countries have already decided to continue with their regular seasonal vaccination campaigns to protect vulnerable individuals  from the risk of contracting a seasonal influenza infection from A(H3N2) or B viruses.

Apart from the evidence coming from serological studies, between August and November 2009, four observational studies investigating the effect of seasonal influenza vaccination on the risk of infection with 2009 pandemic influenza have been published [1,5-7]. Three of these studies indicated no significant effect of the seasonal vaccine against infection with the pandemic virus and one showed a protective vaccine effect. The main findings of these four studies are described below.

The first study was conducted in Australia and measured vaccine effectiveness against laboratory-confirmed medically attended influenza-like illness (ILI). A total of 577 patients were included, of whom 212 (37%) had confirmed pandemic influenza virus infection. ILI patients who tested negative for influenza acted as controls. The study found no effect of the seasonal vaccine against the pandemic virus. Age adjusted VE was 3% (95% CI -56 to 40) for all patients, 10% (95% CI -54 to 48) in patients aged 5–49 years and 1% (95% CI -70 to 42) in patients aged 20–64. The Australian system has provided credible seasonal vaccine effectiveness estimates in the past using the same methodological approach [1,8].

The second study was conducted in the US and used a case-cohort design comparing seasonal vaccination coverage among persons with H1N1 2009 infection with the estimated seasonal vaccination coverage in the general population. For the case group, authors used surveillance reports from eight States of persons aged > 18 years with rRT-PCR-confirmed pandemic H1N1 illness during May and June 2009. Estimates for the population cohort were based on influenza vaccination coverage for the same States during the 2008/2009 influenza season by using preliminary Behavioral Risk Factor Surveillance Survey (BRFSS) data. Vaccine effectiveness (VE) was calculated as VE = 1 − relative risk (RR), where RR was the overall RR of pandemic influenza (H1N1) 2009 illness by seasonal vaccination status. Overall vaccine effectiveness against pandemic influenza infection after adjustment for age group and presence of chronic medical conditions was -10% (95% CI = -43% to -15%). Vaccine effectiveness in age groups varied from -57% (30–39 years old) to 15% (40–49 years old), the CIs for each age group were wider than for the overall VE due to reduced sample sizes within age strata [7].

The third study is an analysis conducted within an outbreak investigation in a large university in Delaware, USA. Assessing the effectiveness of seasonal vaccination against pandemic H1N1 2009 was one of the secondary objectives of the investigation and details of the vaccine effectiveness analysis are not described in the article. However, within the large study population included (7 150 subjects with information available on prior seasonal vaccination), there was no difference in risk of ILI between vaccinated and unvaccinated individuals. After adjusting for age and presence of a chronic condition, there was no difference in the risk of ILI between vaccinated and unvaccinated subjects (RR, 1.1; 95% CI 0.9 to 1.4) [6].

The fourth study was conducted in a single hospital in Mexico and measured vaccine effectiveness against hospitalisation for confirmed pandemic influenza (H1N1) 2009. A total of 240 patients were included, of whom 60 were patients with laboratory-confirmed influenza A(H1N1)v infection and 180 were controls admitted to the hospital with other diseases. The study found a protective vaccine effectiveness of 73% (95% CI 34% to 89%) [5]. This is not in a system that has regularly been used to estimate vaccine effectiveness and some experts in the field of seasonal vaccine effectiveness studies have recently questioned the methodological soundness of the Mexican study [9].

All four presented studies differ in terms of study design, study quality and ability to adjust for confounding factors. It is perhaps not surprising that one of them shows a discordant result pointing towards some effectiveness of the seasonal vaccine against infection with the pandemic virus.

Various types of confounding factors and bias can affect influenza vaccine effectiveness measures in both directions giving rise to falsely low or high vaccine effectiveness. For example, in the study conducted in Mexico, controls were more likely than cases to be vaccinated for seasonal influenza given the higher proportion of individuals with chronic conditions among controls than among cases. Thus, even in the absence of any real vaccine effectiveness, observational studies can still show a positive or negative effectiveness only because of methodological problems. Furthermore, there are various factors that influence the estimation of vaccine effectiveness and that can especially occur during a pandemic when care-seeking behaviours are quite likely to change. Therefore, when conducting vaccine effectiveness studies during a pandemic, the impact of different confounding factors and more biases than usual introduced by the unusual pandemic context have to be considered.

On balance, the information available from the four published epidemiological studies plus the serological study results do not support any change in the seasonal or pandemic influenza vaccination policies by EU Member States.

All influenza viruses may cause serious illness and vaccination is the most important counter-measure for protecting against seasonal and pandemic influenza. Even though the risk from A(H3N2) and B viruses would seem to be less than usual this coming season – and almost non-existent from seasonal A(H1N1) – it is prudent to continue to offer seasonal influenza immunisation to all older individuals and to all individuals older than six months belonging to certain groups who are at high risk of having serious seasonal flu-related complications as per Member State recommendations [10,11]. This is also consistent with the recommendations of WHO and CDC to continue with seasonal influenza vaccination. At the same time, the wide circulation of pandemic influenza virus in Europe, the data on its severity in certain risk groups [10,11] and the good safety and efficacy profile of pandemic vaccines strongly support the continuation of pandemic vaccination programmes in Europe. Many individuals belong to risk groups that are the same for seasonal and pandemic influenza disease. For these individuals, administration of both vaccines is advised and any opportunity for vaccination should be used to administer them.

References

[1] Kelly H, Grant K. Interim analysis of pandemic influenza (H1N1) 2009 in Australia: surveillance trends, age of infection and effectiveness of seasonal vaccination. Euro Surveill 2009;14(31).

[2] Belgian working group on influenza A(H1N1)v. Preliminary analysis of influenza A(H1N1)v individual and aggregated case reports from EU and EFTA countries. Euro Surveill 2009 Jun 11;14(23):19238.

[3] Hancock K, Veguilla V, Lu X, Zhong W, Butler EN, Sun H, et al. Cross-reactive antibody responses to the 2009 pandemic H1N1 influenza virus. New Engl J Med 2009 Nov 12;361(20):1945-52.

[4] Serum cross-reactive antibody response to a novel influenza A (H1N1) virus after vaccination with seasonal influenza vaccine. MMWR 2009 May 22;58(19):521-4.

[5] Garcia-Garcia L, Valdespino-Gomez JL, Lazcano-Ponce E, Jimenez-Corona A, Higuera-Iglesias A, Cruz-Hervert P, et al. Partial protection of seasonal trivalent inactivated vaccine against novel pandemic influenza A/H1N1 2009: case-control study in Mexico City. BMJ 2009;339:b3928.

[6] Iuliano AD, Reed C, Guh A, Desai M, Dee DL, Kutty P, et al. Notes from the field: outbreak of 2009 pandemic influenza A (H1N1) virus at a large public university in Delaware, April–May 2009. Clin Infect Dis 2009 Dec 15;49(12):1811-20.

[7] Effectiveness of 2008–09 trivalent influenza vaccine against 2009 pandemic influenza A (H1N1) – United States, May–June 2009. MMWR 2009 Nov 13;58(44):1241-5.

[8] Kelly H, Carville K, Grant K, Jacoby P, Tran T, Barr I. Estimation of influenza vaccine effectiveness from routine surveillance data. PloS one. 2009;4(3):e5079.

[9] Janjua NZ, Skowronski DM, Hottes TS, De Serres G, Crowcroft NS, Rosella LC. Selection bias explains seasonal vaccine's protection. BMJ. 2009;339:b4972.

[10] VENICE project report, available at http://venice.cineca.org/reports.html.

[11] European Centre for Disease Prevention and Control. Q&A on vaccines and vaccination in relation to the pandemic influenza (H1N1) 2009. 9 November 2009. Available at: http://www.ecdc.europa.eu/en/healthtopics/Documents/0911_Pandemic_Influenza_(H1N1)_QA_on_Vaccines_and_Vaccination_Experts.pdf