Influenza Clinical Trial
Official title:
Effectiveness of the GSK Pandemic H1N1 Influenza Vaccines in Preventing Hospitalization for Influenza and Pneumonia in Manitoba, Canada
Excellent immune responses following 1 or 2 doses of the GSK monovalent AS03-adjuvanted
pandemic H1N1 (pH1N1) vaccines (e.g., Arepanrix®) have been documented in several trials.
Observational studies have found that these vaccines were effective in preventing laboratory
confirmed influenza infections. However, it remains unclear whether vaccination during the
pandemic was associated with reductions in more clinically meaningful outcomes, such as
hospitalizations, severe illness, complications, and death.
The investigators propose to evaluate the effectiveness of the GSK adjuvanted and
non-adjuvanted pH1N1 vaccines used in Manitoba in preventing hospitalization and severe
illness (defined as illness necessitating admission to intensive care or associated with
major complications) due to influenza or pneumonia by means of a case-control study using
data from Manitoba Health (MH) administrative databases and the database of the Cadham
Provincial Laboratory. The primary outcome will be hospitalization with laboratory-confirmed
influenza or pneumonia. A secondary outcome will be hospitalization with influenza or
pneumonia. The investigators will also assess the effectiveness of the above vaccines for
different age groups and among high-risk populations, e.g., immunocompromised individuals.
Testing for influenza is largely discretionary because most patients presenting with
influenza-like illness (ILI) could be effectively and safely managed even when the diagnosis
is not confirmed. So, it is unclear whether reduction in the risk of laboratory-confirmed
influenza or mild ILI among vaccinated individuals is of much clinical significance. In
contrast, hospitalization due to influenza or pneumonia is usually not as discretionary, and
from both clinical and public health perspectives avoiding hospitalization is more important
and relevant objective for influenza control than the mere reduction of laboratory-confirmed
cases.
Thus far there have been few observational studies that examined the effectiveness of the
H1N1 vaccine against hospitalization, and most of them had significant limitations including
small sample sizes, information limited to certain age groups (e.g., children) and the
potential for selection and recall bias. Using data from a Scottish general practice sentinel
surveillance network, Simpson et al reported that the adjuvanted GSK vaccine was 95%
(76-100%) effective against laboratory-confirmed H1N1 infections, and 100% (∞-100%) effective
against hospitalization for influenza and pneumonia. Unexpectedly, the vaccine was equally
effective among 'high-risk' groups. Small number of cases limited the precision of these
estimates; the above-mentioned estimate for vaccine effectiveness (VE) against
hospitalization is based on a one case only, which is the reason for the wide confidence
interval that is compatible with any VE estimate (∞-100%). A hospital-based case-control
study from Spain showed that use of several pandemic vaccines was associated with 90%
effectiveness in preventing laboratory-confirmed H1N1 infections among hospitalized patients.
That study was not population-based and was limited by small number of fully-vaccinated
subjects (only 7 subjects received a pandemic vaccine ≥ 7 days before symptom onset).
Two Canadian studies examined the effectiveness of the GSK adjuvanted H1N1 vaccine: one was
very small (28 cases) and was limited to children under 10 years. The study by Skowronski et
al. that used data from the Canadian VE sentinel network did not examine VE against
hospitalization and it, too, was very small.
In the Canadian province of Manitoba, mass immunization against pandemic H1N1 commenced
October 26th 2010 using primarily large scale vaccination clinics led by public health teams
and lasted approximately 8 weeks. Initially, the Canadian-manufactured Arepanrix®, an
AS03-adjuvanted split virion pandemic H1N1 vaccine (GlaxoSmithKline [GSK]), was used to
vaccinate adults and children over 6 months of age. Later on, two nonadjuvanted vaccines,
from CSL Limited and GSK, were offered to pregnant women and children over 10 years of age.
The seasonal trivalent inactivated influenza vaccines (TIV)—Fluviral® (GSK) and Vaxigrip®
(Sanofi Pasteur) — were less frequently administered.
All vaccines were offered free of charge, but limited vaccine supply at campaign start
necessitated the development of priority groups for early vaccination. The initial priority
group in Manitoba included health care workers, Aboriginal persons, pregnant women, 6-60
months-old children, individuals under 65 years with chronic medical conditions,
immunocompromised individuals and residents of remote communities. On November 18,2010, the
pandemic H1N1 vaccines were made available to the whole population.
This study evaluates the effectiveness of the GSK adjuvanted and non-adjuvanted pH1N1
vaccines used in Manitoba in preventing hospitalization and severe illness. The advantages of
the proposed study over the existing literature are related to the availability of
high-quality population-based health administrative databases that cover a well-defined
population. The whole population of Manitoba is eligible and available for inclusion in the
study, so selection bias is not a concern. Ascertainment of cases is virtually complete
because all admitted influenza or pneumonia cases in the province are captured by the
Hospital Abstract database. The availability of detailed histories of vaccination, through
the unique Manitoba Immunization Registry eliminates recall bias, reduces vaccine use
measurement errors (e.g., due to patient confusion about what vaccines were received) and
permits detailed assessments of the effect of the timing of vaccination on the risk of
hospitalization. These detailed analyses will be facilitated by the large sample size (40% of
Manitoba's 1.2 million population were vaccinated).
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