Seasonal Influenza Vaccine and Protection against
Pandemic (H1N1) 2009-Associated Illness among US
Matthew C. Johns1*, Angelia A. Eick2, David L. Blazes1, Seung-eun Lee2, Christopher L. Perdue3, Robert
Lipnick3, Kelly G. Vest1, Kevin L. Russell1, Robert F. DeFraites4, Jose L. Sanchez1
1Division of GEIS Operations, Armed Forces Health Surveillance Center, Silver Spring, Maryland, United States of America, 2Henry M. Jackson Foundation for the
Advancement of Military Medicine, Armed Forces Health Surveillance Center, Silver Spring, Maryland, United States of America, 3Division of Communication, Standards
and Training, Armed Forces Health Surveillance Center, Silver Spring, Maryland, United States of America, 4Armed Forces Health Surveillance Center, Silver Spring,
Maryland, United States of America
Introduction: A novel A/H1N1 virus is the cause of the present influenza pandemic; vaccination is a key countermeasure,
however, few data assessing prior seasonal vaccine effectiveness (VE) against the pandemic strain of H1N1 (pH1N1) virus are
Materials and Methods: Surveillance of influenza-related medical encounter data of active duty military service members
stationed in the United States during the period of April–October 2009 with comparison of pH1N1-confirmed cases and
location and date-matched controls. Crude odds ratios (OR) and VE estimates for immunized versus non-immunized were
calculated as well as adjusted OR (AOR) controlling for sex, age group, and history of prior influenza vaccination. Separate
stratified VE analyses by vaccine type (trivalent inactivated [TIV] or live attenuated [LAIV]), age groups and hospitalization
status were also performed. For the period of April 20 to October 15, 2009, a total of 1,205 cases of pH1N1-confirmed cases
were reported, 966 (80%) among males and over one-half (58%) under 25 years of age. Overall VE for service members was
found to be 45% (95% CI, 33 to 55%). Immunization with prior season’s TIV (VE=44%, 95% CI, 32 to 54%) as well as LAIV
(VE=24%, 95% CI, 6 to 38%) were both found to be associated with protection. Of significance, VE against a severe disease
outcome was higher (VE=62%, 95% CI, 14 to 84%) than against milder outcomes (VE=42%, 95% CI, 29 to 53%).
Conclusion: A moderate association with protection against clinically apparent, laboratory-confirmed Pandemic (H1N1)
2009-associated illness was found for immunization with either TIV or LAIV 2008–09 seasonal influenza vaccines. This
association with protection was found to be especially apparent for severe disease as compared to milder outcome, as well
as in the youngest and older populations. Prior vaccination with seasonal influenza vaccines in 2004–08 was also
independently associated with protection.
Citation: Johns MC, Eick AA, Blazes DL, Lee S-e, Perdue CL, et al. (2010) Seasonal Influenza Vaccine and Protection against Pandemic (H1N1) 2009-Associated
Illness among US Military Personnel. PLoS ONE 5(5): e10722. doi:10.1371/journal.pone.0010722
Editor: Ron A. M. Fouchier, Erasmus Medical Center, Netherlands
Received January 7, 2010; Accepted April 8, 2010; Published May 19, 2010
This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public
domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
Funding: This study was supported by the baseline funding of the US Military’s Defense Health Program for the Armed Forces Health Surveillance Center
(AFHSC). No non-government funding was accepted for this effort. The funders had no role in study design, data collection and analysis, decision to publish, or
preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: firstname.lastname@example.org
Influenza is a common infection among military personnel who
are frequently exposed to a variety of respiratory pathogens in
crowded living conditions, stressful working environments and
during deployments . An annual influenza vaccination policy
was implemented for active duty personnel during World War II,
which subsequently led to the prevention of large influenza
epidemics in military personnel . However, influenza outbreaks
of novel strains have occurred, such as the previous appearance of
a ‘‘swine influenza’’ A/H1N1 strain among soldiers at Fort Dix,
New Jersey, in early 1976,  as well as the ongoing pandemic
caused by a novel influenza A/H1N1 (pH1N1) virus . World
governments and the scientific community have renewed concerns
about a lack of population immunity as well as the reported lack of
cross-protective immunity from seasonal influenza vaccines .
Trivalent inactivated vaccine (TIV) formulations have been in
use by the US military for the past six decades . Live attenuated
influenza vaccine (LAIV) was added during the 2003–04 influenza
season. Since the introduction of LAIV, Department of Defense
(DoD) policy has called for preferential use of LAIV over TIV
stemming from vaccine shortages during the 2003–2004 influenza
season and reported benefits in the young, healthy recruit
populations [6,7]. Recent clinical trials, [8,9] as well as DoD-
based analyses of influenza, influenza-like illnesses and pneumo-
nia-related healthcare encounters, [6,7] suggest that TIV is more
efficacious against laboratory-confirmed influenza among civilians
as well as among highly-immunized military service members.
PLoS ONE | www.plosone.org1 May 2010 | Volume 5 | Issue 5 | e10722
Conversely, previously published AFHSC data also suggest that
LAIV may be just as effective as TIV among vaccine-naı ¨ve
personnel . The primary objective of this effort was to provide
an interim assessment of the effectiveness of a single season’s
(2008–2009) influenza vaccine against clinically-apparent, labora-
tory-confirmed pH1N1-associated illness. The results of this study
will help to develop a mechanism for systematically tracking and
assessing vaccine effectiveness (VE) for the newly available
monovalent H1N1 pandemic vaccine and seasonal influenza
vaccines of the future.
Materials and Methods
Ethics Statement: The AFHSC has been directed by military authorities to
conduct public health surveillance of respiratory infectious diseases and
evaluation of related protection measures. According to 45 CFR 46.101/102,
this activity does not constitute research, thus, institutional review board
examination was not required. No external (non-DoD) funding was used to
conduct this investigation, and contents have been cleared for public release by
the US Army Public Health Command (Provisional).
The surveillance population of interest was all active component
service members (as opposed to those in the National Guard or
Reserves) stationed in the United States at some point during the
period of April 20 through October 15, 2009. Data were obtained
from the Defense Medical Surveillance System (DMSS), a large
relational database that contains longitudinal data including
demographic characteristics, occupations, immunizations and
medical encounters for US military service members . Data
collection begins at the time of entry into service and continues
through the military career. Certain medical conditions of military
relevance, including laboratory-confirmed influenza, are submitted
through electronic notifiable disease reporting systems using case
definitions established by the Armed Forces Health Surveillance
Center (AFHSC) and are part of the DMSS data .
Reporting criteria for influenza was defined as a clinically-
apparent illness (fever, cough and/or sore throat) which was
confirmed by polymerase-chain reaction (PCR). Reports of
confirmed influenza from Army, Air Force and Navy (including
Marine Corps and US Coast Guard) reporting systems were
included as part of the DMSS data.
Cases were defined as active component service members with a
laboratory-confirmed pH1N1-associated illness reported through
one of the service-specific notifiable disease reporting systems.
Controls were defined as active component service members who
reported to the same military treatment facility as their date-
matched case with a diagnosis of a musculoskeletal (International
Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-
CM)=700–739, 810–848, or V54) or a mental health encounter
(ICD-9-CM=700–739, 810–848, or V54) and no documented
respiratory problems (ICD-9-CM=001–139, 320–326, 380–382,
460–519, 780.6, 780.7, 786, or 787.0) during the medical visit.
The control’s medical encounter had to occur within 3 days of the
case’s medical encounter. A maximum of four controls were
matched to each case.
Immunization data from DMSS were used to determine
whether cases and controls received any influenza vaccination
during the influenza season of August 1, 2008 through July 31,
2009. Subjects who received an influenza vaccine at least 14 days
prior to the date of their qualifying medical encounter were
considered immunized; all others (those immunized less than 14
days prior to medical encounter, those vaccinated after the
medical encounter, or those not vaccinated with the current
seasonal influenza vaccine) were considered non-immunized for
the purposes of this evaluation.
Crude odds ratios (OR) were calculated for comparison of cases
to controls by multiple factors including sex, age group (,25, 25 to
29, 30 to 39, 40 and over), race-ethnicity (White, Black, Hispanic,
Asian/Pacific Islander, American/Alaskan Indian, Other/un-
known), service (Army, Air Force, Coast Guard, Navy, Marine
Corps), history of underlying medical conditions (required at least
one prior medical encounter with a primary diagnosis of asthma,
chronic obstructive pulmonary disease, diabetes, chronic renal
disease, cancer, circulatory system conditions, or nervous system
conditions), pregnancy, non-influenza vaccines administered 0–30
days prior to the influenza vaccine, and history of prior influenza
vaccination (yes/no). Adjusted OR (AOR) for vaccination status
was calculated using conditional logistic regression adjusting for
sex, age group, and history of prior influenza vaccination.
Separate stratified VE analyses by age group, vaccine type (TIV
and LAIV) and hospitalization status were performed and VE
estimates were adjusted for sex, age group (except for the age
stratified analysis), and history of prior vaccination. VE was
defined as (1 – OR *100) as previously published  the adjusted
odds ratios for LAIV and TIV in the vaccine stratified analysis
were tested for homogeneity using a conditional logistic regression
model. All analyses were performed using SAS 9.1.3 (SAS
Institute, Cary, North Carolina, USA).
During the period April 20, 2009 to October 15, 2009, a total
of 1,205 clinically-apparent, laboratory-confirmed pH1N1-asso-
ciated illnesses were reported. Case subjects were similar to
controls with the exception of age; mean and median age for
cases and controls was found to be 25.3 and 23 years compared
to 30.2 and 28 years, respectively, Cases were also noted to have
received fewer vaccines in prior years than controls (Table 1).
Controls were more likely to have a history of an underlying
medical condition compared to cases (46% versus 24%,
subjects were also more likely to have a history of an underlying
medical condition compared to unvaccinated subjects (For Cases:
27% versus 11%; For Controls: 47% versus 36%). However,
since having history of an underlying medical condition was
highly correlated with age and receipt of prior influenza vaccine
during 2004–08 (two variables already included in the adjusted
model), this variable had no effect on the VE estimate when
added to the model and was therefore not include in the final
adjusted model. Additionally, no differences were seen in the
percent of cases and controls who received non-influenza
vaccines within the 30-days prior to the influenza vaccine and
none of the subjects were pregnant. Cases were distributed over a
wide geographic range with most (74%) reported in six states
(Texas, n=511; California, n=128; South Carolina, n=73;
Florida, n=68; North Carolina, n=58; and, Missouri, n=49)
and the remaining 318 cases distributed among 26 additional
states (AK, AR, AZ, CO, DC, GA, HI, IL, KS, KY, LA, MA,
MD, ME, MS, ND, NE, NJ, NM, NY, OH, OK, SD, VA, WA
Overall, a moderate association with protection with any 2008–
09 seasonal influenza vaccine was observed with a VE of 45%
(95% CI, 33 to 55%) (Table 2). Age-stratified analyses revealed an
independent, age-associated effect. Younger and older individuals
(,25 years, VE=50%; 40+ years, VE=55%) exhibited a
markedly higherVE estimate
(VE=26%) or 30–39 years (VE=9%) (Table 3). In addition,
prior vaccination in 2004–08 timeframe (VE=41%, 95% CI, 29
to 51%) was also significantly associated with protection (Table 4).
Seasonal Flu Vaccine and pH1N1
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In the stratified analysis of vaccine-specific effectiveness, both
TIV and LAIV were found to be associated with protection
(Table 5). The adjusted VE estimate ranged from 44% (95% CI,
32 to 54%) to 24% (95% CI, 6 to 38%) for TIV and LAIV,
respectively. The association with protection provided by TIV was
not found to be statistically significantly different from LAIV
Over88%of the hospitalizationsoccurredover a seven-week period
in June and July of 2009. Assessment of VE with regards to disease
severity showed there to be a higher association with protection
against more severe outcomes (e.g., for those hospitalized). This
association with protection was greater among hospitalized cases
(62%) compared to non-hospitalized cases (42%) (Table 6).
The results of this assessment suggest there is an association with
protection from the northern hemisphere 2008–09 seasonal
influenza vaccine against clinically-apparent, laboratory-con-
firmed pH1N1-associated illness among active component US
military service members. This association with protection may be
more apparent for hospitalized (more severe) outcomes and
warrants further investigation. Our findings further complement
recent reports among civilian populations in Mexico [13,14] and
among health care professional in Ontario, Canada  that
demonstrate moderate to high (35 to 73%) vaccine effectiveness
against pH1N1-associated illness from seasonal influenza vaccina-
tion. A very recent report from a Singaporean prospective study
 indicated a marked increased risk of pH1N1 infection in
military personnel and has also provided further evidence of an
association with protection from seasonal influenza vaccines
among military personnel when compared to civilian populations.
In contrast, published findings from Australia,  and three
US-based studies [18–20] showed either negligible association
with protection (overall VE=210 to 3%, 95% CI, 256 to 40%).
Moreover, one recently published study out of Canada docu-
mented an increased risk for medically-attended, laboratory-
confirmed pH1N1 after receipt of seasonal vaccine (VE=268%,
95% CI, 2174 to 3%) . The health care encounter-related
findings of our vaccine effectiveness assessment also expand
further on recently published laboratory-based serologic studies of
the effect of TIV vaccines against pH1N1 [22–24].
Our data also suggests that prior receipt of TIV or LAIV
induces an association of protection against pH1N1-associated
illness. This may reflect ‘‘priming’’ of the humoral immune system
with influenza vaccine as demonstrated in immunologically-naı ¨ve
children [25,26]. Similar findings have also been observed in US
military populations where the influenza vaccine increased the
effectiveness of preventing pneumonia and influenza morbidity
among vaccine-naı ¨ve service members compared to service
members routinely immunized . Our findings also expand on
the observations by Ohmit, et al,  and Monto, et al,  in their
prospective, randomized, double-blind, placebo-controlled, 4-year
study of efficacy demonstrating that TIV offers a higher degree of
protection against laboratory-confirmed influenza in years 1
(2004–05) and 4 (2007–08) of their study.
Like the US CDC’s recently published US serologic data [22–
24] our findings also strongly suggest an age-related association
with protection. However, it appears that any association with
protection may actually occur in those as young as 17 to 24 years
of age. An unexpected finding of our study was the increased
association with protection in those 40 years of age and older,
perhaps reflecting an association with previous vaccine exposure
and/or natural infection with other human H1N1 viruses in the
setting of crowded living conditions prevalent in the military
environment or in the population old enough to have been
exposed to 1918-like H1N1 viruses [1,27,28,29]. There are reports
Table 1. Univariate Analysis and Characteristics of pH1N1
Cases and Controls.
Male 966 (80.2) 3584 (74.5) 1.39 (1.19–1.63)
Female 239 (19.8) 1226 (25.5)Ref
,25 696 (57.8)1572 (32.7) Ref
25–29 289 (24.0)1058 (22.0)0.59 (0.50–0.70)
30–39151 (12.5) 1398 (29.1) 0.23 (0.19–0.28)
69 (5.7) 782 (16.3) 0.18 (0.14–0.24)
White 691 (57.3) 3054 (63.5)Ref
Hispanic 151 (12.5)496 (10.3) 1.36 (1.11–1.66)
Black235 (19.5) 884 (18.4)1.19 (1.00–1.41)
Asian/Pacific Islander74 (6.1) 172 (3.6)1.92 (1.44–2.56)
American Indian/Alaskan Native 14 (1.2) 53 (1.1) 1.19 (0.66–2.15)
Other/Unknown 40 (3.3)151 (3.1)1.18 (0.82–1.68)
Army445 (36.9) 1908 (39.7)Ref
Air Force527 (43.7) 2012 (41.8)1.56 (1.18–2.07)
Navy 88 (7.3)295 (6.1) 1.81 (1.22–2.70)
Marine Corps 130 (10.8)541 (11.2) 1.25 (0.81–1.92)
Coast Guard15 (1.2)54 (1.1) 1.55 (0.65–3.71)
Number of prior vaccinations
0 443 (36.8) 872 (18.1) Ref
762 (63.2)3938 (81.9)0.33 (0.28–0.38)
Note: OR=Odds Ratio.
Table 2. Crude and Adjusted OR for Any Vaccine Received in 2008–2009.
Cases, n (%) Controls, n (%)Crude OR (95% CI)Adjusted OR (95% CI)* Vaccine Effectiveness (95% CI)
Yes956 (79.3)4291 (89.2) 0.43 (0.36–0.51)0.55 (0.45–0.67) 45% (33 to 55%)
No 249 (20.7)519 (10.8) Ref Ref Ref
*Adjusted for sex, age group, and number of prior vaccinations.
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of cross-reactive protection induced by vaccination and infection
with virus strains that are divergent between, and within, influenza
A virus subtypes in animal models. It seems likely that, in addition
to induced hemagglutinin (HA) strain-specific antibody responses,
that cross-reactive epitopes on the HA and neuraminidase (NA)
external proteins, as well as, immune responses to epitopes on
internal proteins can contribute to protection against influenza
[30–35]. In addition to these specific epitopes, other studies have
suggested that neutralizing capability depends also on the affinity
and avidity of the antibodies such that quality may be more of a
factor than quantity alone [36–39]. To what degree host-specific,
genetically-determined immune responses further confound vac-
cine effectiveness (or efficacy) has not been adequately studied and
may represent an important biological/host confounder which is
difficult to address in epidemiologic studies such as this.
Additional findings from our study support the notion that
vaccination with seasonal influenza vaccines in the preceding four
years (2004–08) also conferred a certain degree of protective
immunological memory relevant to the new viral strain. Indeed,
it has been shown in previous studies that both humoral and cell-
mediated immune (CMI) responses may contribute to protection
in influenza-vaccinated persons. In animal studies, the role of
CMI in viral clearance and host survival has been shown and
increasing evidence is available regarding T cell-mediated
immune responsesin humans
vaccination [40,41]. Thus, it is reasonable to think that CMI
plays a significant role and that cross-protective CMI to pH1N1
virus may actually exist in individuals who have been frequently
immunized and/or exposed to seasonal influenza . As
recently described by Greenbaum, et al,  it is also possible
that some degree of pre-existing ‘‘memory’’ conferred by
exposure to T-cell epitopes, similar to those found in previously
circulating H1N1 strains in the past 20 years (1988–2008), may
indeed work to elicit increased immunity of adults. This
observation may explain the cumulative enhanced benefit of
multiple prior influenza vaccines overlapping with increased
potential seasonal exposures in older subjects.
There are several limitations with this study. First, tobacco
exposure (e.g., smoking), an important co-factor in increasing the
risk for influenza infection/disease, was not addressed in this study.
There is animal, laboratory-based  and human epidemiologic-
based evidence  which strongly suggests smoking as an
important factor in predisposing to influenza infection and/or
pneumonia. It is possible that lower rates of tobacco use among
older military populations contrasted with higher use among
younger military personnel outside of basic training (where
after natural infectionor
Table 3. Crude and Adjusted OR for Specific Age-Groups for Any Vaccine Received in 2008–2009.
Cases, n (%)Controls, n (%)Crude OR (95% CI) Adjusted OR (95% CI)** Vaccine Effectiveness (95% CI)
Age group, ,25 years
Yes 507 (72.8)1344 (85.5) 0.45 (0.37–0.57)0.50 (0.40–0.63) 50% (37 to 60%)
No 189 (27.2) 228 (14.5)Ref RefRef
Age group 25–29 years
Yes 259 (89.6) 959 (90.6) 0.89 (0.58–1.37)1.06 (0.68–1.67)
26% (267 to 32%)
No 30 (10.4)99 (9.4) Ref RefRef
Age group 30–39 years
Yes136 (90.1) 1272 (91.0) 0.90 (0.51–1.58)0.91 (0.51–1.63)9% (263 to 49%)
No 15 (9.9)126 (9.0)Ref RefRef
Age group 40+ +
Yes 54 (78.3)716 (91.6)0.33 (0.18–0.62) 0.45 (0.22–0.93) 55% (7 to 78%)
No 15 (21.7)66 (8.4) Ref Ref Ref
**Adjusted for sex and number of prior vaccinations.
Table 4. Crude and Adjusted OR for Service Members with a Documented History of Receiving Previous Influenza Vaccines.
Number of prior vaccinations (2004–2008)
0 443 (36.8) 872 (18.1)Ref RefRef
762 (63.2) 3938 (81.9)0.33 (0.28–0.38) 0.59 (0.49–0.71) 41% (29 to 51%)
Note: OR=Odds Ratio.
***Adjusted for sex and age group.
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tobacco use is more controlled) may have been an important
confounder not adjusted for in this study.
Second, the vaccination status was based upon electronic data
and relied on reporting by the vaccinating health care providers.
The possibility of misclassification of vaccine status exists.
However, we believe this to be minimal and non-differential
between the cases and controls. Furthermore, this potential
limitation would bias our results towards the null, therefore
underestimating the overall effectiveness of the vaccines.
Third, it is possible that misclassification of cases into the
control group may have occurred. Since laboratory testing
requirements for pH1N1 confirmation have changed over the
time period of this study (starting with universal testing to only
testing severe cases), and since physicians may not have requested
confirmatory testing for all suspected cases, the possibility exists
that a control subject may have been infected with pH1N1 but did
not get recorded as a laboratory-confirmed case. In order to
decrease this risk of misclassification we excluded from our
potential control pool anyone who had a wide range of
respiratory-associated symptoms or diagnoses during their quali-
fying medical encounter. However, if this misclassification did
occur we expect it would be non-differential in nature and, again,
bias our results toward the null.
Fourth, both cases and controls were highly vaccinated; 80%
and 89%, respectively. Thus, it is possible that the minority of the
service members who did not receive the 2008–09 seasonal
vaccine may have differed in the risk for influenza if they suffered
from predisposing, co-morbid conditions which may have
increased their risk of infection and/or illness as previously
described . However, similar to findings from observational
studies among the elderly, we actually found that vaccinated
subjects were more likely to have history of an underlying medical
condition compared to unvaccinated subjects [47–49]. This could
have potentially biased our study results towards the null (e.g. less
VE), however, when added to the model we found this had no
effect on the VE estimates due to the high correlation with age and
prior receipt of an influenza vaccine.
Lastly, there are a number of studies that clearly illustrate the
inherent bias in assessing influenza vaccine effectiveness when
conducting observational, cross-sectional studies such as ours
[50,51]. Inherent biases in case ascertainment and access to care
may have taken place, however, we feel these potential biases were
minimized due to our study population. The active component
military population receives universal health care coverage at
military treatment facilities regardless of the nature of their
underlying conditions or presenting medical symptoms (e.g., equal
access to care for respiratory and non-respiratory complaints) and
thus, would not have influenced our results in a significant manner.
Our finding of a greater association with protection against
severe illness (e.g., hospitalization) suggests that the northern
Table 5. Vaccine-specific Crude and Adjusted OR for Cases Received the 2008–2009 Trivalent Influenza Vaccine (TIV) or Live
Attenuated Influenza Vaccine (LAIV).
Cases, n (%) Controls, n (%) Crude OR (95% CI) Adjusted OR (95% CI)* Vaccine Effectiveness (95% CI)
Yes440 (63.9)2063 (79.9)0.44 (0.37–0.53) 0.56 (0.46–0.68)44% (32 to 54%)
No 249 (36.1) 519 (20.1) Ref RefRef
Yes 505 (67.0)2166 (80.7)0.49 (0.41–0.58)0.76 (0.62–0.94) 24% (6 to 38%)
No 249 (33.0) 519 (19.3)Ref RefRef
Note: OR=Odds Ratio.
*Adjusted for sex, age group, and number of prior vaccinations.
Figure 1. Number of Hospitalized and Non-hospitalized pH1N1 Cases by Week.
Light Bars=Non-Hospitalized Cases.Dark
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hemisphere 2008–09 influenza vaccine may have a more
significant impact against overt pH1N1-associated illness com-
pared to subclinical infection. This warrants further analysis with a
larger sample size looking at age, sex, race and other factors,
specifically for hospitalized individuals. Prospective monitoring of
health care outcomes which may be indicative of severe pH1N1-
associated illness, such as severe acute respiratory infections
(SARI) and pneumonia is being implemented among all
beneficiaries of the military health system.
Ongoing, systematic evaluations of seasonal and pH1N1-
specific vaccination programs are critical to assess the overall
public health impact of these interventions. Our data supports the
importance of continued immunization coverage for all popula-
tions as recently recommended by the CDC’s Advisory Committee
on Immunization Practices . Expanded assessment of vaccine
effectiveness among high-risk recruit populations who are
immunologically-naı ¨ve and who traditionally sustain higher rates
of acute respiratory infections,  as well as, among young
children and high-risk adults, are indicated and may further refine
understanding of biological diversity based on age, sex and
background disease states. In addition, the role of multiple
previous influenza vaccines on immune response and vaccine
efficacy/effectiveness deserves further investigation.
Further studies of the potential association between prior seasonal
and pH1N1-specific influenza vaccinations (either single- or multi-
year reception) and seasonal as well as pH1N1-associated illnesses are
needed and should include prospective cohort as well as retrospective
case-control studies using sentinel surveillance data [17,53,54]. In
addition, future immunologic assessments of any age-related
protective effect (possibly due to the presence of natural infection or
vaccine-induced cross-reactive antibodies) should also be conducted
to furtherelucidatethisrelationship.Agreater numberofcaseswith a
broader, older age representation are needed to study these
hypotheses more thoroughly. In addition, the role of sex differences
on vaccine immune responses and associated efficacy/effectiveness
estimations needs to be evaluated through epidemiologic studies .
In summary, a moderate association with protection against
clinically-apparent, laboratory-confirmed pH1N1-associated ill-
ness was found for immunization with either TIV or LAIV
seasonal influenza vaccines. This association with protection was
greater for severe disease as compared to milder outcomes. There
was also a greater association with protection in the youngest (,25
years) and oldest (40+ years) compared to those 25 to 39 years.
Prior vaccination in the 2004–08 timeframe was also indepen-
dently associated with protection. Cross-protective immunity, as a
result of natural influenza infections or prior influenza immuni-
zation in the military setting, may play a role in conferring a
certain degree of enhanced host immunity as exposure takes place
with each subsequent influenza season strain(s). Therefore, it is
important to examine host-specific, genetically-determined factors
in future assessments of influenza vaccine efficacy and/or
We want to extend our great appreciation and gratitude to the staff at the
Data Analysis Division, AFHSC, for their technical assistance in data
compilation and analysis; to Dr. David Shay, Influenza Division, Centers
for Disease Control and Prevention (CDC) and Dr. David Tribble,
Infectious Disease Clinical Research Program, for their insightful ideas and
suggestions; to COL Renata Engler, Vaccine Healthcare Centers Network,
Walter Reed Army Medical Center and Dr. Frank Ennis, University of
Massachusetts School of Medicine, for their contributions to the
immunological aspects of the discussion; to Dr’s Joel Gaydos, Ronald
Burke and John Brundage of the AFHSC for their critique and manuscript
review; to Dr. Mark Duffy at the United States Air Force School of
Aerospace Medicine for provision of Air Force data and Ms. Asha
Riegodedios at the Navy and Marine Corps Public Health Center for
provision of study data; and, to all service component public health
personnel who manage and report medical events data to the AFHSC.
Disclaimer: The opinions and assertions contained herein are solely those
of the authors and do not reflect the official policy or position of the US
Department of Defense (DoD) or of its subordinate services (Army, Navy or
Air Force) medical authorities.
This work was partially presented at the 58thAnnual Meeting of the
American Society of Tropical Medicine and Hygiene, Washington, DC on
November 19, 2009 and at the International Symposium for Respiratory
Viral Infections, Taipei, Taiwan on March 15, 2010.
Conceived and designed the experiments: MCJ AAE DLB JLS. Analyzed
the data: MCJ AAE SEL RJL JLS. Wrote the paper: MCJ JLS. Technical
support: DLB CLP. Analysis and interpretation of the data: DLB. Editing
of manuscript: DLB KGV. Critical interpretation of the data: SEL.
Manuscript drafting: SEL. Critical review of the draft manuscript: CLP.
Senior scientific oversight: RJL KLR. Critical review and assistance in final
drafting of the manuscript: RJL KGV JLS. Senior guidance: KLR. Senior
scientific leadership and institutional guidance: RFD. Senior oversight
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Table 6. Crude and Adjusted OR for Hospitalized and Non-hospitalized Cases and Controls.
Cases, n Controls, n Crude OR (95% CI)Adjusted OR (95% CI)*Vaccine Effectiveness (95% CI)
Hospitalized, any Vaccine
Yes44 276 0.15 (0.08–0.29) 0.38 (0.16–0.86) 62% (14 to 84%)
Non-hospitalized, any Vaccine
Yes 9124015 0.48 (0.39–0.57)0.58 (0.47–0.71) 42% (29 to 53%)
No215 483 Ref Ref Ref
Note: OR=Odds Ratio.
*Adjusted for sex, age group, and number of prior vaccinations.
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