Title

Author(s)

Efficacy of dual vaccination of pandemic H1N1 2009 influenza

and seasonal influenza on institutionalized elderly : a one-year
prospective cohort study
Chan, Tuen-ching;

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2011

http://hdl.handle.net/10722/144852

The author retains all proprietary rights, (such as patent rights)

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Efficacy of dual vaccination of pandemic H1N1 2009 influenza and

seasonal influenza on institutionalized elderly: a one-year prospective
cohort study

By

Dr CHAN Tuen Ching

This work is submitted to

Faculty of Medicine of The University of Hong Kong
In Partial fulfillment of the requirements for
The Postgraduate Diploma in Infectious Diseases, PDipID (HK)

Date: 24 February 2011

Supervisor: Professor Woo PCY

Declaration

I, Chan Tuen Ching, declare that this dissertation represents my own work and that it
has not been submitted to this or other institution in application for a degree, diploma
or any other qualifications.
I, Chan Tuen Ching also declare that I have read and understand the guideline on
What is plagiarism? published by The University of Hong Kong (available at
http://www.hku.hk/plagiarism/) and that all parts of this work complies with the
guideline.
Candidate: Chan Tuen Ching
Signature:_________________
Date:_________________

Abstract
Background
The influenza A (H1N1) 2009 pandemic was declared by the WHO in April 2009. In
Hong Kong, the vaccination program began in December 2009 in addition to the
annual seasonal trivalent influenza vaccination program. The clinical efficacy of dual
vaccination was unknown.

Method
From December 2009 to November 2010, a prospective 12-month cohort study on
institutionalized elderly of nine residential care home for elderly (RCHE) was
conducted. Elderly persons who were followed up by the Hong Kong West
Community Geriatric Assessment Team and had been vaccinated by the Department
of Health were included. Outcome measures included all cause mortality and
hospitalization.

Results
711 elderly persons were included. 274 received both seasonal influenza vaccine and
(H1N1) 2009 vaccine (H1N1-TIV), 368 received seasonal influenza vaccine only
(TIV alone) and 69 received no vaccination (unvaccinated). Baseline characteristics

were well matched between the groups, except there were fewer females in the TIV
alone. The 12-month mortality rates of the H1N1-TIV, TIV alone and unvaccinated
were 10.6%, 19.8% and 29% respectively. Multivariate analysis demonstrated that
dual vaccination in the institutionalized elderly significantly reduced all cause
mortality by 54% (Hazard Ratio [HR] 0.46; 95% confidence interval [CI] 0.29-0.72;
p<0.001) and 74% (HR 0.26; CI 0.13-0.49; p<0.001), compared with vaccination of
seasonal vaccination alone and no vaccination respectively. Dual vaccination also
reduced the rate of hospitalization per year compared with seasonal vaccination alone
(0.95 vs 1.30; p<0.05) and unvaccinated group (0.95 vs 1.52; p<0.05).

Conclusion
Dual vaccination with both H1N1 and seasonal vaccinations provided additional
protection to institutionalized elderly in reducing mortality and hospitalization.

Keywords
Efficacy, Influenza A (H1N1) 2009, vaccination, mortality, hospitalization,
institutionalized elderly

Background

In June 2009, the World Health Organization declared the novel strain of swine-origin
Influenza A (H1N1) 2009 as pandemic. Over 14 months, more than 18000 deaths of
laboratory confirmed (H1N1) 2009 were reported from 214 countries (1). In Hong
Kong, the first case of (H1N1) 2009 was confirmed on 1/5/2009. Up till 8/2010, the
Center for Health Protection (CHP) in Hong Kong had recorded a total of 294 severe
(H1N1) 2009 resulting in 81 fatalities (2).

The elderly is one of the most at risk population for seasonal influenza infection and
influenza related mortality (3). Nevertheless, epidemiological studies on the novel
(H1N1) 2009 suggested otherwise, with the majority of hospitalized and severe cases
in children and young adults, probably a result of the lack of preexisting
cross-reactive antibodies against the (H1N1) 2009 in patients born after 1950. Less
than 5% of the hospitalization for this novel virus aged >65 (4). It appeared that
elderly are less vulnerable in this pandemic. However, a majority of affected elderly
lived in the residential care home for elderly (RCHE), who had multiple underlying
chronic medical conditions. Institutionalized elderly was still the major at risk group
among all aged >65. In order to protect this vulnerable population, the Hospital

Authority (HA)/CHP launched a mass vaccination program for the (H1N1) 2009 in
December 2009, which covered all elderly persons aged 65 years or above, those with
chronic illness, health care workers, pregnant women, and children between the age of
6 months and 6 years.

At the same time, annual seasonal trivalent influenza vaccination program was
launched from October 2009. Although (H1N1) 2009 vaccine was shown to be safe
and able to induce satisfactory immune response (5-8), the clinical efficacy of dual
vaccination of (H1N1) 2009 and seasonal influenza was unknown. We therefore
decided to perform a prospective study to investigate the efficacy of dual vaccination
in institutionalized elderly on mortality and hospitalization.

Methodology
Study Design
We performed a prospective cohort study to assess the efficacy of dual vaccination of
(H1N1) 2009 monovalent vaccine and trivalent seasonal vaccine in institutionalized
elderly on mortality and hospitalization, from December 2009 to November 2010. All
participants gave informed consent for vaccination of trivalent seasonal influenza in
October and November 2009 and vaccination of (H1N1) 2009 in December 2009. The
study was conducted in accordance with the Declaration of Helsinki (9). The research
was formally approved by the institutional review boards at the University of Hong
Kong and Hospital Authority Hong Kong West Cluster (HKWC).

Study Sites and Participants

The study was performed in HKWC, one of the seven major health districts in Hong
Kong under the Hospital Authority, which provides public hospital service for all
Hong Kong citizens. In 2009, the population of HKWC was over 530,000 (10) and
there were over 70 RCHEs, taking care of more than 6000 elderly. Many
institutionalized elderly have limited mobility or advanced medical diseases that limit
their ability to attend outpatient clinic. Community Geriatric Assessment Team
(CGAT) of HKWC, including geriatrician, geriatric nurse specialist and community

nurse provide comprehensive outreach service for them and take care of their medical
illness. More than 3000 elderly were under their management in 2009.

Apart from CGAT that provide management for medical illness, the Department of
Health of Hong Kong provide annual vaccination program for elderly living in RCHE.
In 2009, seasonal influenza vaccination program was carried out from October. The
vaccine for seasonal influenza 2009 was a trivalent influenza vaccine containing 15g
haemaglutinin of the following strain: an A/Brisbane/59/2007 (H1N1)-like virus, an
A/Brisbane/10/2007 (H3N2)-like virus and a B/Brisbane/60/2008-like virus. Influenza
A (H1N1) 2009 vaccination was carried out in December of 2009. The vaccine used
for (H1N1) 2009 was Panenza (Sonofi Pasteur, France), a monovalent inactivated,
non-adjuvanted vaccine formulated to contain 15g hemagglutinin (HA) of influenza
A/California/07/2009 (H1N1) virus.

In order to minimize selection bias, nine RCHE were included, which were all Care
and Attention Home (C&A Home), operated by the government or charitable
non-profit making organization. They have comparable caregiver to elderly ratio.

The inclusion criteria were elderly aged 65 or above, living in one of the nine RCHE

and were followed up by CGAT. They were divided into 3 groups according to the
participants choice of vaccination. The first group was elderly consented to have both
trivalent seasonal influenza vaccination and monovalent (H1N1) 2009 vaccination
(H1N1-TIV group) .The second group was elderly consented to have trivalent
seasonal influenza vaccination only (TIV only group). The third group was elderly
who refused both vaccinations (unvaccinated group). Elderly who were diagnosed to
have advanced malignancy prior to the start of this study in December 2009 were
excluded.

Data collection
Vaccination statuses were collected from patient records of RCHE. Patient records of
RCHE have documentation of vaccination status of each resident every year even if
resident have vaccination done in private sector.

Baseline demographic data, including gender and age had been collected through
computer management system (CMS) and patient consultation record. The CMS has
record of comorbidity standardized on the basis of The International Classification of
Disease, Ninth Revision, Clinical Modification (ICD-9-CM). CMS also has record of
patient demographic, any hospitalization, medication use, laboratory result and death

for all patients registered in the system. All elderly followed up by CGAT were
registered in the system.

Number and type of co-morbidity on the basis of ICD-9-CM were quantified using
Charlson Co-morbidity index (CCI). CCI was first introduced in 1987. Each
co-morbidity is assigned with a score of 1, 2, 3 or 6 depending on the risk of dying
associated with this condition (11-12). It is a valid and reliable method to measure
co-morbidity that can be used in clinical research (13-14).

Functional status of patient was assessed by the Barthel Index 20 [BI(20)]. The BI(20)
is a validated functional scale that measures performance in basic activities of daily
living (15). It has 10 variables describing activities of daily living and mobility. It was
first introduced in 1965 and it is regarded as reliable tool for measuring functional
states of patients and thence is widely used (16). Two doctors performed updated
BI(20) on all screened patient from August 2009 to October 2009.

Hospital admissions documented in CMS between the December 2008 and November
2009 were recorded and regarded as admission in the preceding year.

The clinical status of patients was monitored half yearly from July 2009 to December
2010 by retrieving patient records and CMS. Hospitalization and reasons of
hospitalization were noted. Only hospitalization for acute condition was counted,
including consultation to department of Accident and Emergency and hospitalization
due to acute condition. Scheduled clinical admission was excluded. Mortality of
patients and cause(s) of death were also studied.

Outcome measure
Outcomes were all cause mortality rate and rate of hospitalization for acute condition
over 12 months.

Statistics
Statistical Package for Social Science (Windows version 18; SPSS Inc, Chicago,
United States) was used in statistical analysis. Continuous valuables were expressed
as either mean standard deviation of the mean (mean SD) if they are normally
distributed or median with interquartile range if their distribution is skewed.
Independent t test was used to compare the change of continuous variables of two
different groups. Analysis of variance (ANOVA) was used to compare the change of
continuous variables for 3 different groups if the valuables were normally distributed.

Kruskal-Wallis test was used to compare the change of continuous variables for 3
different groups if the distribution of valuables was skewed. Chi-square test and
Fishers exact test were employed to compare categorical variables. The effectiveness
of the vaccine in the prevention of mortality was estimated using multivariable Cox
proportional hazard models, which we adjusted for covariables. Age, gender, CCI, BI,
vaccination status for (H1N1) 2009, seasonal influenza and pneumococcus were
considered as covariates. Kaplan-Meier curves were constructed to illustrate the
cumulative rate of mortality between groups during the 12-month follow up.
Statistical significance was inferred by a two-tailed p value of 0.05 or less.

Results
711 elderly were included in the study. 274 (38.5%) of them had vaccination of both
seasonal influenza and (H1N1) 2009 (H1N1-TIV group). 368 (51.8%) had
vaccination of seasonal influenza only (TIV alone group). 69 (9.7%) of them had not
received both vaccination (unvaccinated group).

There was no significant difference among the 3 groups for age, CCI, BI(20) and
hospitalization in preceding year. The distribution of gender is different in the 3
groups. 66.7% of elderly were female in H1N1-TIV group, while 61.6% of elderly
were female in TIV alone group and 71.5% of elderly were female in unvaccinated
group. (Table 1)

Part I Death
At 12 months of study, 10.6% (29 of 274) of elderly in H1N1-TIV group died, 19.8%
(73 of 368) of elderly in TIV alone group died, 29% (20 of 69) of elderly in
unvaccinated group died. Comparison by log rank test showed there was significant
difference. (p<0.001) (Figure 1) Based on this mortality rate in the 3 groups, the
absolute risk reduction of H1N1-TIV group, compared with TIV alone group and
unvaccinated group, was 9.2% (19.8% - 10.6%) and 18.4% (29% - 10.6%)

respectively. The number of institutionalized elderly needed to receive dual

vaccination to prevent one death (NNT) was 11 and 6, compared with TIV alone
group and unvaccinated group respectively.

Between H1N1-TIV and TIV alone group

Dual vaccinees had a significantly lower mortality than TIV alone group after
univariate analysis (Relative Risk [RR], 0.51; 95% confidence interval [CI], 0.33-0.78;
p<0.001). Multivariate analysis using Cox proportional hazard models was then
performed by entering age, gender, CCI and BI as covariate. The hazard ratio of
mortality for H1N1-TIV group was 0.46 (CI, 0.29-0.72; p<0.001). Dual vaccinees had
a 54% reduction in mortality when compared with TIV alone group.

Between H1N1-TVI group and unvaccinated group

Dual vaccinees had a significantly lower mortality than unvaccinated group after
univariate analysis (RR 0.31; 95% CI 0.18-0.55; p<0.001). Multivariate analysis using
Cox proportional hazard models was then performed. The hazard ratio of mortality for
dual vaccinees was 0.26 (CI, 0.13-0.49; p<0.001). Dual vaccinees had a 74%
reduction in mortality when compared with unvaccinated group.

Between TIV alone group and unvaccinated group

TIV alone group had a trend of lower mortality than unvaccinated group after
univariate analysis. There was a 39% reduction in mortality (RR 0.62; 95% CI
0.38-1.01; p=0.051).

Part II Rate of Hospitalization

Dual vaccinees had a significantly lower rate of all cause hospitalization when
compared with TIV alone group (0.95 vs 1.30 hospitalization per year; p<0.05). Dual
vaccinee also had a significantly lower rate of all cause hospitalization when
compared with unvaccinated group (0.95 vs 1.52 hospitalization per year; p<0.05).
(Figure 2)

Discussion

Influenza can cause significant morbidity and mortality. For all influenza related
deaths, about 90% occur among people aged 65 years or above (17). However, the
vaccination rate for this pandemic (H1N1) 2009 was very low. Compared with >80%
vaccination rate for seasonal influenza in our study, only 38.2% of institutionalized
elderly had (H1N1) 2009 vaccinated. There were many possible reasons for the low
vaccination rate. Fear of side effects was one of the major reasons (18-19). The
occurrence of suspected cases of major adverse event, including Guillain-Barre
Syndrome, increased the perceived risk of injection in public and decreased its
acceptance. In addition, a low perceived danger for this pandemic, with less than 5%
of hospitalization involved people aged >65 years, made institutionalized elderly less
eager for vaccination.

Although the vaccination rate for (H1N1) 2009 was quite low, its efficacy had been
reassured in this study by reducing all cause mortality and hospitalization. The results
suggested that dual vaccination of (H1N1) 2009 and seasonal influenza in
institutionalized elderly significantly reduced all cause mortality by 54% and 74%,
compared with vaccination of seasonal vaccination alone and unvaccinated group

respectively. The NNT to prevent one death was 11 and 6 only, compared with TIV
alone group and unvaccinated group respectively. In 2010, there are more than 40000
elderly living in RCHEs in Hong Kong. 100% coverage could prevent thousands of
death.

Despite there was no major outbreak of influenza A (H1N1) 2009 in RCHE, mortality
and morbidity from influenza is often attributed to secondary bacterial infection,
cerebrovascular accident and cardiovascular condition such as ischemic heart disease.
Up to 13.8 percent of deaths from ischemic heart disease are associated with influenza
(20). Influenza may predispose to increased risk of ischemic heart disease through
alterations in circulating clotting factors, platelet aggregation and lysis (21-25). A
monitoring of mortality and hospitalization can indirectly assess the efficacy of
influenza vaccine.

Finding of this study is very important for public health issue. (H1N1) 2009 have
become part of epidemic influenza and annual influenza vaccination program of 2010
has included (H1N1) 2009. A reassuring result on the efficacy of vaccination of
(H1N1) 2009 will not only increase confidence and acceptance of the vaccine in
institutionalized elderly and their relative, but also increase the confidence and

acceptance of the vaccine in the general public. It may increase vaccination rate in
coming years and may help to reduce influenza-related mortality.

A major strength of this study was the involvement of functional assessment, frailty
assessment and co-morbidity assessment. Systematic review in 2007 suggested there
was a chance of overestimation of efficacy of seasonal influenza vaccination because
an increase in vaccination coverage from 15% to 65% over 2 decades could not
document a reduction in mortality attributed to influenza (26-27). Systematic review
had suggested the major reason for possible overestimation from cohort studies is
frailty selection bias. Frailty selection bias means a subset of under vaccinated and
very frail elderly people have contributed a substantial proportion of all deaths studied.
During data collection, this study included updated functional status measurement by
using BI(20), updated frailty assessment by using hospitalization in preceding year
and updated co-morbidity assessment by using CCI. By involving these three
important confounding factors during data collection and subsequent multivariate
analysis, it reduced the chance of over-estimation of the efficacy of vaccine. To our
knowledge, this is the first prospective cohort for efficacy of influenza vaccine that
has simultaneously included the three confounding factors.

There were some limitations in this study. The participants were not randomized
because of ethical reason. The CCI was quantified based on ICD coding in CMS,
which may be underestimated. However, the possibility of under-coding present in all
3 groups, bias contributed by it is non-differential in nature. We also focused our
study on patient living in C&A home in HKWC only and did not include privately
operated RCHE or C&A home in other cluster. However, there were strict criteria for
patient referred for follow up in CGAT, their functional status and CCI scoring were
similar. It allowed generalization of our finding into elderly living in other RCHE. In
term of outcome measurement, we did not included data collection for laboratory
confirmed influenza, which is a direct evidence for influenza infection and allow
direct estimation of vaccination efficacy. Measurement of all cause mortality and
hospitalization can only provide an indirect estimation of efficacy of influenza
vaccination. Besides, the samples included in our study were institutionalized elderly,
the frailest elderly group with multiple co-morbidity and poor functional status. The
mortality was up to 10% in 1-year time. It prevented generalization of finding to all
elderly living in community. However, finding from this study emphasized that proper
vaccination is essential for this frailest group. Last but not the least, there was only a
trend in reduction of mortality when compared TIV alone group with unvaccinated
group. It may be due to the sample size in unvaccinated group was not large enough

to detect a significant difference. On the other hand, the sample size in H1N1-TIV
group and TIV alone group were large enough to detect a significant difference in
mortality between them.

In conclusion, this prospective cohort suggested that dual vaccination of (H1N1) 2009
and seasonal influenza in the institutionalized elderly significantly reduced all cause
mortality by 54% and 74%, compared with vaccination of seasonal vaccination alone
and unvaccinated group respectively. Dual vaccination also reduced all causes of
hospitalization compared with seasonal vaccination alone and the unvaccinated group.
The Department of Health should make further effort to let the public realize this
finding to increase confidence and acceptance of the vaccine in institutionalized
elderly, their relative and general public.

Acknowledgements
We gratefully acknowledge all our health care colleagues in the Hospital Authority
who participated in this study.

Conflict of interest
The authors declare no financial conflicts of interest.

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Table 1. Baseline Characteristics of the 711 study subjects

H1N1-TIVa
(n=274)

TIV alone

Age

p valueb

(n=368)

Unvaccinated
group (n=69)

85.97.4

85.97.5

84.48.7

0.26

Gender (female)

66.7%

61.6%

71.5%

0.032*

Hospitalization in
preceding year

1 (0-2)

1 (0-2)

1 (0-3)

0.85

Charlson Comorbdity
index

2.9 1.4

2.9 1.5

2.6 1.5

0.29

11

20

16

0.08

11

14

0.29

0.88

16

17

13

0.62

27

29

26

0.82

0.92

77

74

68

0.25

44

39

32

0.14

0.89

3 (1-10)

4 (1-15)

4 (1-12)

0.052

Ischemic Heart
Disease (%)
Chronic Pulmonary
Disease (%)
Chronic Liver
Disease (%)
Congestive Heart
Failure (%)
Diabetes (%)
Peripheral Vascular
Disease (%)
Dementia (%)
Cerebrovascular
Disease (%)
Chronic Renal
Impairment (%)

BI score

*Significant
a. Data are mean standard deviation if valuable are normally distributed or median
(interquartile range) if the distribution of valuable are skewed
b. Analysis of variance (ANOVA) was used if the valuables were normally
distributed. Kruskal-Wallis test was used if the distribution of valuables was
skewed.

Figure Legends
Figure 1. Overall cumulative survival of 3 groups of patient after vaccination*
*Comparison by log rank test <0.001, aUnvaccinated: No vaccination of H1N1(2009)
or seasonal influenza, bTIV alone: Vaccination of seasonal influenza only, cH1N1-TIV:
Vaccination of both H1N1(2009) and seasonal influenza

Figure 2 Rate of hospitalization of the 3 groups of patient after vaccination*

*Comparison by ANOVA p<0.001, aUnvaccinated: No vaccination of H1N1(2009) or
seasonal influenza, bTIV alone: Vaccination of seasonal influenza only, cH1N1-TIV:
Vaccination of both H1N1(2009) and seasonal influenza

Figures
Figure 1

Figure 2.

Appendix I
Charlson Comorbidity Indx by using ICD-9-CM
Scoring

Comorbidity

Myocardial Infarction
Congestive Heart Failure
Peripheral Vascular Disease
Cerebrovascular Disease
Dementia
Chronic Pulmonary Disease
Chronic Rheumatic Disease
Peptic Ulcer Disease
Mild Liver Disease
Diabetes Without Chronic Complication

Diabetes With Chronic Complication

Hemiplegia
Renal Disease
Tumor Without Metastasis

Moderate Or Severe Liver Disease

Metastatic Solid Tumor

AIDS