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H1n1 Vaccine Research Papers

How effective is the flu vaccine?

CDC conducts studies each year to determine how well the influenza (flu) vaccine protects against flu illness. While vaccine effectiveness can vary, recent studies show that flu vaccination reduces the risk of flu illness by between 40% and 60% among the overall population during seasons when most circulating flu viruses are well-matched to the flu vaccine. In general, current flu vaccines tend to work better against influenza B and influenza A(H1N1) viruses and offer lower protection against influenza A(H3N2) viruses. See “Does flu vaccine effectiveness vary by type or subtype?” and “Why is flu vaccine typically less effective against influenza A H3N2 viruses?” for more information.

What are factors that influence how well the vaccine works?

How well the flu vaccine works (or its ability to prevent flu illness) can range widely from season to season. The vaccine’s effectiveness also can vary depending on who is being vaccinated. At least two factors play an important role in determining the likelihood that flu vaccine will protect a person from flu illness: 1) characteristics of the person being vaccinated (such as their age and health), and 2) the similarity or “match” between the flu viruses the flu vaccine is designed to protect against and the flu viruses spreading in the community. During years when the flu vaccine is not well matched to circulating influenza viruses, it is possible that no benefit from flu vaccination may be observed. During years when there is a good match between the flu vaccine and circulating viruses, it is possible to measure substantial benefits from flu vaccination in terms of preventing flu illness. However, even during years when the flu vaccine match is good, the benefits of flu vaccination will vary, depending on various factors like the characteristics of the person being vaccinated, what influenza viruses are circulating that season and even, potentially, which flu vaccine was used.

Each flu season researchers try to determine how well flu vaccines work as a public health intervention. Estimates of how well a flu vaccine works can vary based on study design, outcome(s) measured, population studied and the season in which the flu vaccine was studied. These differences can make it difficult to compare one study’s results with another’s.

While determining how well a flu vaccine works is challenging, in general, recent studies have supported the conclusion that flu vaccination benefits public health, especially when the flu vaccine is well matched to circulating flu viruses.

What are the benefits of flu vaccination?

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Is the flu vaccine effective against all types of flu and cold viruses?

Seasonal flu vaccines are designed to protect against infection and illness caused by the three or four influenza viruses (depending on vaccine) that research indicates will be most common during the flu season. “Trivalent” flu vaccines are formulated to protect against three flu viruses, and “quadrivalent” flu vaccines protect against four flu viruses. Flu vaccines do NOT protect against infection and illness caused by other viruses that can also cause flu-like symptoms. There are many other viruses besides flu viruses that can result in flu-like illness* (also known as influenza-like illness or “ILI”) that spread during the flu season. These non-flu viruses include rhinovirus (one cause of the “common cold”) and respiratory syncytial virus (RSV), which is the most common cause of severe respiratory illness in young children, as well as a leading cause of death from respiratory illness in those aged 65 years and older.

Does flu vaccine effectiveness vary by type or subtype?

Yes.  The amount of protection provided by flu vaccines may vary by influenza virus type or subtype even when recommended flu vaccine viruses and circulating influenza viruses are alike (well matched). Since 2009, VE studies looking at how well the flu vaccine protects against medically attended illness have suggested that when vaccine viruses and circulating flu viruses are well-matched, flu vaccines provide better protection against influenza B or influenza A (H1N1) viruses than against influenza A (H3N2) viruses. A study[505 KB, 10 pages] that looked at a number of VE estimates from 2004-2015 found average VE of 33% (CI = 26%–39%) against H3N2 viruses, compared with 61% (CI = 57%–65%) against H1N1 and 54% (CI = 46%–61%) against influenza B viruses. VE estimates were lower when vaccine viruses and circulating viruses were different (not well-matched). The same study found pooled VE of 23% (95% CI: 2% to 40%) against H3N2 viruses when circulating influenza viruses were significantly different from (not well-matched to) the recommended influenza A(H3N2) vaccine component.

Why is flu vaccine typically less effective against influenza A(H3N2) viruses?

There are a number of reasons why flu vaccine effectiveness against influenza A(H3N2) viruses may be lower.

  1. While all influenza viruses undergo frequent genetic changes, the changes that have occurred in influenza A(H3N2) viruses have more frequently resulted in differences between the virus components of the flu vaccine and circulating influenza viruses (i.e., antigenic change) compared with influenza A(H1N1) and influenza B viruses. That means that between the time when the composition of the flu vaccine is recommended and the flu vaccine is delivered, H3N2 viruses are more likely than H1N1 or influenza B viruses to have changed in ways that could impact how well the flu vaccine works.
  2. Growth in eggs is part of the production process for most seasonal flu vaccines. While all influenza viruses undergo changes when they are grown in eggs, changes in influenza A(H3N2) viruses tend to be more likely to result in antigenic changes compared with changes in other influenza viruses. These so-called “egg-adapted changes” are present in vaccine viruses recommended for use in vaccine production and may reduce their potential effectiveness against circulating influenza viruses. Other vaccine production technologies, e.g., cell-based vaccine production or recombinant flu vaccines, could circumvent this shortcoming associated with the use of egg-based candidate vaccine viruses in egg-based production technology, but CDC also is using advanced molecular techniques to try to get around this short-coming.
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How effective is the flu vaccine in the elderly?

Older people with weaker immune systems often have a lower protective immune response after flu vaccination compared to younger, healthier people. This can make them more susceptible to the flu. Although immune responses may be lower in the elderly, vaccine effectiveness has been similar in most flu seasons among older adults and those with chronic health conditions compared to younger, healthy adults.

If older people have weaker immune responses to flu vaccination, should they still get vaccinated?

Despite the fact that older adults (65 years of age and older) have weaker immune responses to vaccine flu vaccines, there are many reasons why people in that age group should be vaccinated each year.

  • First, people aged 65 and older are at increased risk of serious illness, hospitalization and death from the flu.
  • Second, while the effectiveness of the flu vaccine can be low among older people, there are seasons when significant benefit can be observed. Even if the vaccine provides less protection in older adults than it might in younger people, some protection is better than no protection at all, especially in this high risk group.
  • Third, flu vaccine may protect against more serious outcomes like hospitalization and death. For example, one study concluded that one death was prevented for every 4,000 people vaccinated against the flu.
  • In frail elderly adults, hospitalizations can mark the beginning of a significant decline in overall health and mobility, potentially resulting in loss of the ability to live independently or to complete basic activities of daily living. While the protection elderly adults obtain from flu vaccination can vary significantly, a yearly flu vaccination is still the best protection currently available against the flu.
  • There is some data to suggest that flu vaccination may reduce flu illness severity; so while someone who is vaccinated may still get infected, their illness may be milder.
  • Fourth, it’s important to remember that people who are 65 and older are a diverse group and often are different from one another in terms of their overall health, level of activity and mobility, and behavior when it comes to seeking medical care. This group includes people who are healthy and active and have responsive immune systems, as well as those who have underlying medical conditions that may weaken their immune system and their bodies’ ability to respond to vaccination. Therefore, when evaluating the benefits of flu vaccination, it is important to look at a broader picture than what one study’s findings can present.

How effective is the flu vaccine in children?

Vaccination has consistently been found to provide a similar level of protection against flu illness in children to that seen among healthy adults.

In one study, flu vaccine effectiveness was higher among children who received two doses of flu vaccine the first season that they were vaccinated (as recommended) compared to “partially vaccinated” children who only received a single dose of flu vaccine. However, the partially vaccinated children still received some protection.

Flu vaccine can prevent severe, life-threatening illness in children, for example:

  • A 2014 study showed that flu vaccine reduced children’s risk of flu-related pediatric intensive care unit (PICU) admission by 74% during flu seasons from 2010-2012.
  • In 2017, a study in the journal Pediatrics was the first of its kind to show that flu vaccination also significantly reduced a child’s risk of dying from the flu. The study, which looked at data from four flu seasons between 2010 and 2014, found that flu vaccination reduced the risk of flu-associated death by half (51 percent) among children with underlying high-risk medical conditions and by nearly two-thirds (65 percent) among healthy children.

How are benefits of vaccination measured?

Public health researchers measure how well flu vaccines work through different kinds of studies. In “randomized studies,” flu vaccination is randomly assigned, and the number of people who get flu in the vaccinated group is compared to the number that get flu in the unvaccinated group. Randomized studies are the “gold standard” (best method) for determining how well a vaccine works. The effects of vaccination measured in these studies is called “efficacy.” Randomized studies are expensive and are not conducted after a recommendation for vaccination has been issued, as withholding vaccine from people recommended for vaccination would place them at risk for infection, illness and possibly serious complications. For that reason, most U.S. studies conducted to determine the benefits of flu vaccination are “observational studies.”

“Observational studies” compare the occurrence of flu illness in vaccinated people compared to unvaccinated people, based on their decision to be vaccinated or not. This means that vaccination of study subjects is not randomized. The measurement of vaccine effects in an observational study is referred to as “effectiveness.”

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How does CDC present data on flu vaccine effectiveness?

CDC typically presents vaccine effectiveness (VE) as a single point estimate: for example, 60%. This point estimate represents the reduction in risk provided by the flu vaccine. CDC vaccine effectiveness studies measure two outcomes: laboratory confirmed flu illness that results in a doctor’s visit or laboratory-confirmed flu that results in hospitalization. For these outcomes, a VE point estimate of 60% means that the flu vaccine reduces a person’s risk of an outcome by 60%.

In addition to the VE point estimate, CDC also provides a “confidence interval” (CI) for this point estimate, for example, 60% (95% CI: 50%-70%). The confidence interval provides a lower boundary for the VE estimate (e.g., 50%) as well as an upper boundary (e.g., 70%). One way to interpret a 95% confidence interval is that if CDC were to repeat this study 100 times, 95 times out of 100, the true VE value would fall within the confidence interval (i.e., on or between 50% and 70%). There is still the possibility that five times out of 100 (a 5% chance) the true VE value could fall outside of the 50%-70% confidence interval.

Why are confidence intervals important for understanding flu vaccine effectiveness?

Confidence intervals are important because they provide context for understanding the precision or exactness of a VE point estimate. The wider the confidence interval, the less exact the point value estimate of vaccine effectiveness becomes. Take, for example, a VE point estimate of 60%. If the confidence interval of this point estimate is 50%-70%, then we can have greater certainty that the true protective effect of the flu vaccine is near 60% than if the confidence interval was 10-90%. Furthermore, if a confidence interval crosses zero, for example, (-20% to 60%), then the point value estimate of VE provided is “not statistically significant.” People should be cautious when interpreting VE estimates that are not statistically significant because such results cannot rule out the possibility of zero VE (i.e., no protective benefit). The width of a confidence interval is related in part to the number of participants in the study, and so studies that provide more precise estimates of VE (and consequently, have a narrower confidence interval) typically include a large number of participants.

Is it true that getting vaccinated repeatedly can reduce vaccine effectiveness?

Some studies do suggest that flu vaccine effectiveness may be higher in people receiving flu vaccine for the first time compared to people who have been vaccinated more than once; other studies have found no evidence that repeat vaccination results in a person being less-protected against flu.

Immune responses to vaccination may be higher among people who were not vaccinated in a previous season, but repeatedly vaccinated people (i.e., people who receive the flu vaccine each year) may still have increased immune responses after vaccination.

Two reviews of multiple studies have found that for people vaccinated in the prior season, vaccination in the subsequent season provides additional protection against flu.

Information regarding flu vaccination history is particularly important to these types of evaluations, and can be difficult to confirm, as accurate vaccination records are not always readily available. People who choose to get vaccinated every year may have different characteristics and susceptibility to flu compared to those who do not seek vaccination every year. CDC thinks that these findings merit further investigation to understand the immune response to repeat vaccination. CDC supports continued efforts to monitor the effects of repeat vaccination each year. However, based on the substantial burden of flu in the United States, and on the fact that most studies point to vaccination benefits, CDC recommends that yearly flu vaccination remains the first and most important step in protecting against flu and its complications.

Why are there so many different outcomes for vaccine effectiveness studies?

Vaccine effectiveness studies that measure different outcomes are conducted to better understand the different kinds of benefits provided by vaccination. Ideally, public health researchers want to know how well flu vaccines work to prevent illness resulting in a doctor visit, or illness resulting in hospitalization, and even death associated with the flu, to evaluate the benefits of vaccination against illness of varying severity.  Because estimates of vaccine effectiveness may vary based on the outcome measured (in addition to season, population studied and other factors), results should be compared between studies that used the same outcome for estimating vaccine effectiveness.

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How does CDC measure how well the vaccine works?

Scientists continue to work on better ways to design, conduct and evaluate non-randomized (i.e., observational) studies to assess how well flu vaccines work. CDC has been working with researchers at universities and hospitals since the 2003-2004 flu season to estimate how well flu vaccine works through observational studies using laboratory-confirmed flu as the outcome. These studies currently use a very accurate and sensitive laboratory test known as RT-PCR (reverse transcription polymerase chain reaction) to confirm medically-attended flu virus infections as a specific outcome. CDC’s studies are conducted in five sites across the United States to gather more representative data. To assess how well the vaccine works across different age groups, CDC’s studies of flu vaccine effects have included all people aged 6 months and older recommended for an annual flu vaccination. Similar studies are being done in Australia, Canada and Europe. More recently, CDC has set up a second network the Hospitalized Adult Influenza Vaccine Effectiveness Network (HAIVEN) that looks at how well flu vaccine protects against flu-related hospitalization among adults aged 18 and older.

What do recent vaccine effectiveness studies show?

CDC conducts studies each year to determine how well the flu vaccine protects against flu illness. These estimates provide more information about how well this season’s vaccine is working. Recent studies show vaccine can reduce the risk of flu illness by between 40-60% among the overall population during seasons when most circulating flu viruses are well matched to the flu vaccine.

Do recent vaccine effectiveness study results support flu vaccination?

The large numbers of flu-associated illnesses and deaths in the United States, combined with the evidence from many studies that show flu vaccines help to provide protection, support the current U.S. flu vaccination recommendations. It is important to note, however, that how well flu vaccines work will continue to vary each year, depending especially on the match between the flu vaccine and the flu viruses that are spreading and causing illness in the community, as well as the characteristics of the person being vaccinated.

Where can I get more information?

CDC has compiled a list of selected publications related to vaccine effectiveness.

Besides vaccination, how can people protect themselves against the flu?

Getting a flu vaccine each year is the best way to prevent the flu. Antiviral drugs are an important second line of defense against the flu. These drugs must be prescribed by a doctor. In addition, good health habits, such as covering your cough and frequently washing your hands with soap, can help prevent the spread of the flu and other respiratory illnesses.

More information on Vaccine Selection.

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While how well the flu vaccine works can vary, there are many reasons to get a flu vaccine each year.

  • Flu vaccination can keep you from getting sick with flu.
  • Flu vaccination can reduce the risk of flu-associated hospitalization, including among children and older adults.
    • Vaccine effectiveness for the prevention of flu-associated hospitalizations was similar to vaccine effectiveness against flu illness resulting in doctor’s visits in a comparative study published in 2016.
  • Flu vaccination is an important preventive tool for people with chronic health conditions.
    • Flu vaccination has been associated with lower rates of some cardiac (heart) events among people with heart disease, especially among those who experienced a cardiac event in the past year.
    • Flu vaccination also has been associated with reduced hospitalizations among people with diabetes (79%) and chronic lung disease (52%).
  • Vaccination helps protect women during and after pregnancy. Getting vaccinated can also protect a baby after birth from flu. (Mom passes antibodies onto the developing baby during her pregnancy.)
    • A study that looked at flu vaccine effectiveness in pregnant women found that vaccination reduced the risk of flu-associated acute respiratory infection by about one half.
    • There are studies that show that flu vaccine in a pregnant woman can reduce the risk of flu illness in her baby by up to half. This protective benefit was observed for several months after birth.
  • And a 2017 study was the first of its kind to show that flu vaccination can significantly reduce a child’s risk of dying from influenza.
  • Flu vaccination also may make your illness milder if you do get sick. (For example a 2017 study showed that flu vaccination reduced deaths, intensive care unit (ICU) admissions, ICU length of stay, and overall duration of hospitalization among hospitalized flu patients.)
  • Getting vaccinated yourself also protects people around you, including those who are more vulnerable to serious flu illness, like babies and young children, older people, and people with certain chronic health conditions.

*References for the studies listed above can be found at Publications on Influenza Vaccine Benefits. Also see the Why get a flu vaccine [224 KB, 2 Pages] fact sheet.



The extent to which A(H1N1)pdm09 influenza vaccines prevented hospital admissions with pneumonia and influenza (P&I) during the 2009 pandemic remains poorly understood. We evaluated the effectiveness of the A(H1N1)pdm09 and seasonal influenza vaccines (TIV) used during the 2009 mass vaccination campaign in Manitoba (Canada) in preventing P&I hospitalization.


A population-based record-linkage nested case-control study. Cases (N = 1,812) were persons hospitalized with influenza (ICD-10:J09-J11) or pneumonia (ICD-10:J12-J18) during the study period. Age-, gender- and area of residence-matched controls (N = 7,915) were randomly sampled from Manitoba’s Population Registry. Information on receipt of A(H1N1)pdm09 vaccine and TIV was obtained from the Manitoba Immunization Monitoring System, a province-wide vaccine registry.


Overall, the adjuvanted A(H1N1)pdm09 vaccine was 27% (95%CI 13–39%) effective against P&I hospitalization ≥ 14 days following administration. Effectiveness seemed lower among older (≥ 65 years) adults (10%; −16–30%), particularly when compared to under-5 children (58%; 30–75%). The number-needed-to-vaccinate to prevent 1 P&I admission was lowest among <4 year-olds (928) and ≥65 years (1,721). VE against hospitalization with laboratory-confirmed A(H1N1)pdm09 was 70% (39–85%) overall and (91%; 62–98%) ≥ 14 days following vaccination.


Our data suggest that the adjuvanted A(H1N1)pdm09 vaccine was effective in preventing about 55–60% of P&I hospitalizations among children and younger adults who were at much higher risk of infection. Unfortunately, the vaccine was less effective among 65 or older adults. Despite that the vaccine still had a significant population-based impact especially among the very young (<5) and the older (≥ 65 years).

Citation: Mahmud SM, Bozat-Emre S, Hammond G, Elliott L, Van Caeseele P (2015) Did the H1N1 Vaccine Reduce the Risk of Admission with Influenza and Pneumonia during the Pandemic? PLoS ONE 10(11): e0142754.

Editor: Mohammed Alsharifi, The University of Adelaide, AUSTRALIA

Received: September 4, 2015; Accepted: October 26, 2015; Published: November 23, 2015

Copyright: © 2015 Mahmud et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Data Availability: The data used in this analysis are owned by the Manitoba government. We were given permission to access the data to conduct this analysis. But we did not have permission to share the data. However, any researchers interested in replicating our results can access the data the same way we did by applying for access to the Manitoba government. The process is explained in detail here:

Funding: This work was funded by an investigator-initiated grant from GSK Biologicals to the International Centre of Infectious Disease, Winnipeg, Canada. Funders had no role in designing or conducting the study or in the decision to submit the results for publication. GSK: International Centre of Infectious Disease:

Competing interests: The authors have the following interests: Funded by an investigator-initiated grant from GSK Biologicals to the International Centre of Infectious Disease, Winnipeg, Canada. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.


Worldwide, more than 26 different monovalent A(H1N1)pdm09 vaccines were used during the 2009 influenza pandemic to control the spread of infection and reduce disease burden[1]. In Manitoba (Canada), we found that both adjuvanted and non-adjuvanted vaccines were effective in preventing laboratory-confirmed A(H1N1)pdm09 infections[2], and similar findings were reported for other jurisdictions.[3] However, the extent to which vaccination prevented more clinically meaningful outcomes, such as acute hospital admission due to influenza and pneumonia (P&I), is not known.

Rates of laboratory-confirmed influenza can vary significantly between jurisdictions and with epidemic phase in the same jurisdiction as a function of clinical guidelines, epidemic phase and laboratory workload. By comparison, decisions for hospitalization are less discretionary, and as a result hospitalization rates are a robust indicator of epidemic severity.[4] Arguably, avoiding hospitalization is a more relevant outcome for influenza control efforts than the mere reduction in numbers of laboratory-confirmed infections.

We evaluated the effectiveness of the A(H1N1)pdm09 and seasonal influenza vaccines (TIV) used during the 2009 mass vaccination campaign in Manitoba (Canada) in preventing P&I hospitalization using a case-control design and data from Manitoba’s provincial administrative and laboratory databases. We also assessed vaccine effectiveness (VE) for different age groups and among high-risk populations, e.g., immunocompromised persons.



We conducted a nested case-control study using de-identified records obtained by linking the electronic database of the Manitoba Immunization Monitoring System (MIMS) with the Hospital Separation Abstract database and other Manitoba Health (MH) administrative databases, housed at the Manitoba Centre for Health Policy. MH provides publicly-funded universal healthcare insurance to virtually all of Manitoba’s 1.2 million residents regardless of age or income [5]. Insured services include hospital, physician and preventive services (e.g., immunizations). For administrative purposes, MH maintains several centralized electronic databases that can be linked using a unique health services number. The study was approved by the Research Ethics Board of the University of Manitoba and the governmental Health Information Privacy Committee.

Definition of cases and controls

Anyone 6 months or older who was registered with MH during the study period was eligible for inclusion in the study. The study spanned the period from November 2, 2009 (1 week after the start of mass immunization in Manitoba) to February 7, 2010, two weeks following the last reported A(H1N1)pdm09 case in the province.

Any eligible person who was admitted for ≥24 hours to a hospital in Manitoba with a diagnosis of influenza (ICD-10: J09-J11) or pneumonia (ICD-10: J12-J18) during the study period was included in the cases group. Cases were identified using the Hospital Separation Abstract database, which, since 1971, has recorded all services provided by hospitals in the province, including admissions and day surgeries [6]. The data collected include clinical information such as admission and discharge dates and up to 25 diagnoses and 20 services or procedures, coded using the International Classification of Diseases (ICD-10-CA[7]) and the Canadian Classification of Health Interventions (CCI)[8].

Using risk-set sampling, we matched each case to five controls (persons who have not been admitted to hospital by the index date) who were of the same age, gender and area of residence. The date of admission was considered as the “index date” for cases and for their matched controls. Controls were randomly selected from MH’s Population Registry, a continuously updated database that tracks dates and reasons for the initiation and termination of coverage (e.g., death/migration) for all insured persons.

Determination of vaccination status

For all cases and controls, information on the receipt of the pandemic, seasonal influenza and pneumococcal vaccines during and before the 2009/10 season was obtained from MIMS, a population-based province-wide registry of virtually all vaccines administered to Manitoba residents since 1988 [9]. Information, including vaccine type and date of vaccination, is captured either through direct data entry for vaccines administered by public health staff (who administered most influenza vaccines during the pandemic) or using physician claims data for vaccines administered by physicians [10].

In Manitoba, most pandemic vaccines were administered during a mass immunization campaign that began in October 26, 2009 (Week 43), just one week before the peak of the second pandemic wave [2]. Initially, the Canadian-manufactured Arepanrix® (GlaxoSmithKline), an AS03-adjuvanted split virion monovalent vaccine, was used to vaccinate adults and children over 6 months of age. Later on, two nonadjuvanted vaccines, from GlaxoSmithKline and CSL Limited, were offered to pregnant women and children 10 years or older [11]. All vaccines contained the A(H1N1)pdm09 hemagglutinin antigen derived from the influenza A/California/7/2009 strain recommended by the WHO. A single vaccine dose (15μg/0.5 ml) was recommended for those aged >9 years and 2 half doses given 21 days apart were recommended for children 6 months-9 years old.

All vaccines were offered free of charge, but due to limited supply at campaign start priority was given to certain groups including health care workers, Aboriginal persons, residents of remote communities, pregnant women, 6–60 months-old children, persons under 65 years with chronic medical conditions and all immunocompromised persons. On November 18, 2009, vaccines became available to the whole population [2].

Manitoba’s routine immunization schedule includes seasonal trivalent inactivated influenza vaccines (TIV)—during the study period these were Fluviral® (GlaxoSmithKline) and Vaxigrip® (Sanofi Pasteur)—and several polysaccharide and conjugate pneumococcal (PVs).

Potential confounders

Individuals were assigned to a neighbourhood of residence (neighbourhood clusters within the capital city of Winnipeg and regional health authorities in the rest of the province) based on their postal code as recorded in MH’s Population Registry. Household income quintiles, measured at the level of Census Dissemination areas, were determined using 2006 Canadian census data. Information on pregnancy, comorbidities, propensity to seek health care (measured as the number of hospital and family physician visits in the previous 5 years) was obtained from the Hospital Separation and Physician Claims databases. Previously validated algorithms were used to identify various chronic diseases and other indications for vaccination [12–15]. In addition, Charlson comorbidity scores were calculated using an algorithm validated for administrative databases[16]. Information on the use of antivirals and other medications was obtained from the Drug Program Information Network database, the comprehensive database of all out-of-hospital prescriptions dispensed in Manitoba since 1995 [17].

Influenza testing results were obtained from the database of Cadham Provincial laboratory (CPL), the province’s only public health laboratory. During the study period, influenza testing in Manitoba was completed at CPL using a real-time multiplex reverse-transcription polymerase chain reaction (RT-PCR) assay developed by the National Microbiology Laboratory [18].

Statistical analysis

In the primary analysis, we used conditional logistic regression models to estimate the odds ratio (OR) for the association between the receipt of the adjuvanted A(H1N1)pdm09 vaccine and P&J hospitalization while adjusting for matching and confounding variables. Models were adjusted for income, comorbidity, receipt of seasonal and pneumococcal vaccines, use of neuraminidase inhibitors, frequency of contact with healthcare providers and belonging to a vaccine priority group. VE was estimated as (1-OR) x 100. Similar but separate models were used to estimate the VE of nonadjuvanted pandemic, seasonal and pneumococcal vaccines.

In primed healthy adults, the peak serum antibody levels are typically observed >2 weeks after vaccination [19]. To account for differences in effectiveness by time since vaccination, we classified vaccinated individuals into three groups depending on whether vaccination occurred 1–6, 7–13, or ≥ 14 days before the index date, and contrasted the odds of A(H1N1)pdm09 infection in each group with the odds of infection among the unvaccinated.

In addition, we repeated the adjuvanted A(H1N1)pdm09 vaccine analyses after stratifying by age group, place of residence, epidemic phase (admission before and after the peak), presence of high-risk conditions and belonging to a vaccine priority group. We also assessed for possible effect modification by use of seasonal and pneumococcal vaccines. The statistical significance of adding the interaction terms was assessed using the likelihood ratio test [20].


A total of 1,812 persons met the case definition and were matched to 9,060 controls. About 54% of cases were 65 years or older at diagnosis, and 39% resided in the poorest parts of the province (Table 1). As expected, cases tended to be generally sicker than controls with higher Charlson comorbidity scores (average score of 3 compared to 0 for controls), higher overall chance of having ≥1 diagnosed chronic medical conditions (73% compared to 39% among controls) and more frequent hospitalizations and physician consultations. As a result, cases were also more likely to belong to A(H1N1)pdm09 or TIV priority groups (Table 1).

A similar proportion of cases and controls received the adjuvanted A(H1N1)pdm09 vaccine (about 35%; Table 2), comparable to estimates of vaccine coverage for the entire population from MH (37% [11]) and the 2010 Canadian Community Health Survey (37% [95%CI: 33–41%])[21]. However, only about 28% of both groups received the vaccine ≥14 days before the index date corresponding to a VE estimate (adjusted for matching covariates) of 0.2% (95%CI: −13–12%). After adjusting for important confounders, the corresponding VE estimate was 27% (13–39%). Because of small numbers it was not possible to reliably estimate VE of the nonadjuvanted vaccines. In adjusted models, neither receiving the TIV in the 2008/09 or 2009/10 seasons nor receiving a pneumococcal vaccine at any point before the index date had a significant influence on the risk of hospitalization during the study period (Table 2).

In subgroup analyses (Table 3), there was evidence that the adjuvanted A(H1N1)pdm09 vaccine was less effective in preventing P&I hospitalization among 65 or older adults (10% [−16–30%]) compared to younger age groups, particularly under-5 children (58% [30–75%]). The A(H1N1)pdm09 vaccine was also less effective among those with chronic diseases (14% [−11–34%]; Pinteraction = 0.044) and among those who received the 2008/09 TIV (21% [1–37%]), although the latter finding was not statistically significant (Pinteraction = 0.3). On the other hand, there was a statistically significant difference (Pinteraction = 0.016) in A(H1N1)pdm09 VE between those who also received the 2009/10 TIV (12% [−21–36%]) and those who did not (46% [28–60%]).

Table 3. Estimates of the effectiveness (VE) of the adjuvanted A(H1N1)pdm09 vaccine (when received ≥14 days before the index date) against hospitalization due to influenza or pneumonia by certain demographic and clinical characteristics.

About 8% of the cases and none of the controls tested positive for A(H1N1)pdm09 (Table 4), which is not surprising given provincial guidelines discouraging viral testing unless the patient is very ill. Only 6 controls were tested within 2 weeks of the index date compared to 921 cases. In analyses limited to cases hospitalized with laboratory-confirmed A(H1N1)pdm09, 13% of the cases received an adjuvanted A(H1N1)pdm09 vaccine compared to 25% of the controls (Table 4), corresponding to a VE estimate (adjusted for matching covariates) of 59% (30–76%). The corresponding fully adjusted estimate was 70% (39–85%). VE among those who were vaccinated ≥ 14 days before the index date was higher (91%; 62–98%) than among those who were vaccinated <7 days (46%; −48–81%) or 7–13 days before the index date (61%; −11–86%). Despite small numbers, estimates of VE of the nonadjuvanted A(H1N1)pdm09 vaccine were comparable. On the other hand, there was no evidence that the 2008/09 or the 2009/10 TIVs reduced the risk of hospitalization with laboratory-confirmed A(H1N1)pdm09.


Our data suggest that the adjuvanted A(H1N1)pdm09 vaccine prevented about 55 to 60% of P&I hospitalizations among children and younger adults and a much lower percentage (10–15%) of hospitalizations among 65 or older adults and among those with pre-existing chronic diseases (14%). The vaccine was also effective (70% on average) in preventing hospitalizations with laboratory-confirmed A(H1N1)pdm09 with higher levels of protection achieved >14 days after vaccination.

Excellent immune responses following even one dose of the monovalent split/subunit inactivated pandemic vaccines were documented in several immunogenicity trials [22, 23]. In post-marketing studies, the vaccines were also effective in preventing laboratory-confirmed A(H1N1)pdm09 infections during the pandemic. In a systematic review that was limited to 5 observational studies which met stringent quality criteria, the median VE of monovalent A(H1N1)pdm09 vaccines was about 69% [3]. Similar estimates were observed in studies not included in the review [2, 24].

To our knowledge, this is the first published study to evaluate the effectiveness of the A(H1N1)pdm09 vaccine against admission with P&I during the pandemic. On the other hand, VE against hospitalization with A(H1N1)pdm09 infection was examined in few studies. Using data from a Scottish general practice sentinel surveillance network, Simpson et al reported that the adjuvanted vaccine was 95% (76–100%) effective against laboratory-confirmed A(H1N1)pdm09 [25]. Emborg, et al. estimated, using Danish health databases, that the adjuvanted monovalent vaccine was 44% (−19%–73%) effective in preventing hospitalization with laboratory-confirmed A(H1N1)pdm09 infection among younger (<65) chronically ill people [26]. Steens, et al. found that among persons with underlying medical conditions or ≥ 60 years of age, a single dose of the MF-59 adjuvanted A(H1N1)pdm09 vaccine had VE of 19% (−28–49%) [27].

Higher estimates of VE against P&I hospitalization among children and young adults in our study may reflect the greater contribution of A(H1N1)pdm09 to P&I hospitalization during the pandemic among this age group compared to older adults who generally were less likely to become infected [28, 29]. Also, in a previous analysis from Manitoba we found that the vaccine was more effective in preventing A(H1N1)pdm09 infection in children compared to older adults.[2] This is also consistent with studies that examined VE against hospitalization with A(H1N1)pdm09 among children. In a Quebec study, VE of a single pediatric dose of the same AS03-adjuvanted vaccine that was used in Manitoba, was 85% (61–94%) among 6 month-9 year olds and slightly lower in 5–9 year-olds at 79% (−31–96%) [30]. In a smaller study conducted in New York, a single dose of the nonadjuvanted vaccine was 82% (0–100%) effective in in preventing hospitalization ≥ 14 days after vaccination in children aged 3–9 years [31]. Based on this evidence, it is reasonable to conclude that that the A(H1N1)pdm09 was effective in protecting younger children against hospitalization with P&I during the pandemic.

For older adults, our A(H1N1)pdm09 VE estimates were lower than estimates obtained from observational studies of the effectiveness of TIVs against P&I hospitalization during non-pandemic seasons. In a comprehensive Cochrane review,[32] 8 such studies had a pooled estimate of 26% (12%-38%) during seasons when the vaccine was well matched to the circulating strain. However, our estimates are more in line with the studies that attempted to control for confounding by the “healthy vaccinee effect” (seniors who get vaccinated are on average healthier than those who do not) which produced estimates between 8 and 14%[33–35].

Despite lower VE and lower incidence of A(H1N1)pdm09 among the elderly, our data suggest that only very young children (0–4 years) had a lower number needed to vaccinate (NNV = 928) to prevent one hospital admission for P&I. The NNV among 65 or older was 1,721 compared to 2,273 among 45–64 olds and 7,598 among 25–44 olds. This reflects the much lower overall rate of P&I admissions among the latter two groups (4–5/10,000) compared to 59/10,000 among the ≥65 age group and 19/10,000 among 0–4 year olds. Ignoring potential indirect benefits due to herd immunity, these figures suggest that vaccinating the <5 and ≥65 age groups was more cost-effective than vaccinating other groups.

In our study, the TIVs did not appear to protect against P&I admissions overall or due to A(H1N1)pdm09. This makes sense because in Manitoba the pandemic strain almost entirely replaced previously circulating influenza strains during the 2009/10 season and there was no evidence of significant cross-protective response in previous studies.[36] We observed that the A(H1N1)pdm09 vaccine was less effective among those who also received the 2009/10 TIV. It is unclear whether this reflects a biological effect or confounding by indication because the TIV is indicated to persons at higher risk of developing severe influenza illness and its complications [37]. The issue of whether TIV use before or during the pandemic increased the incidence or severity of A(H1N1)pdm09 remains controversial [38].

Strengths and Limitations

Because of its population-based design and the availability of accurate automated hospital admission and vaccination records, this study is less susceptible to selection and recall biases that commonly afflict conventional case-control studies [10]. Because cases and controls were identified on the basis of comprehensive hospital records with high standards of coding practices,[13] misclassification of hospitalization status is also not a major concern in this study.

We used proxies for access to health care (e.g., frequency of physician encounters) to adjust for factors associated with the likelihood of admission and influenza testing. We also adjusted for confounding by several vaccine indications such as immune status and pre-existing health conditions using information obtained from administrative databases. The completeness and accuracy of the MH database are well established [6, 39], and these databases have been used extensively in studies of post-marketing surveillance of drugs and vaccines [2]. However, it is still possible that some variables were measured with error, which could result in residual confounding. We did not have information on functional status. However, the observed protective effects of A(H1N1)pdm09 vaccination are unlikely to be due to the healthy vaccinee effect, because vaccination was targeted at the higher-risk, and generally less healthy, groups, and we adjusted for vaccine indications in our models. Also, we did not observe any protective effects for the TIVs which are presumably subject to the same bias.

Confounding by herd immunity following the summer wave of the pandemic is also unlikely explanation for our findings, because we adjusted for area of residence in all models and because VE estimates were similar for northern and southern communities despite significant differences in A(H1N1)pdm09 seroprevalence between these communities at the end of the summer wave of the pandemic [28].


Our data suggest that the adjuvanted A(H1N1)pdm09 vaccine was effective in preventing about 55–60% of P&I hospitalizations among children and younger adults who were at much higher risk of infection. Unfortunately, the vaccine was less effective among 65 or older adults. Despite that the vaccine still had a significant population-based impact especially among the very young (<5) and the older (≥ 65 years).


The authors acknowledge the Manitoba Centre for Health Policy for use of data contained in the Population Health Research Data Repository under project “Effectiveness of GSK Pandemic H1N1 Influenza Vaccines in Preventing Hospitalizations for Influenza Pneumonia” (HIPC# 2011-2012-30). The results and conclusions are those of the authors and no official endorsement by the Manitoba Centre for Health Policy, Manitoba Health, Healthy Living, and Seniors, or other data providers is intended or should be inferred.

Author Contributions

Conceived and designed the experiments: SMM GH LE PVC. Analyzed the data: SBE. Wrote the paper: SMM GH LE PVC.


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Key Points

In the recent pandemic, the A(H1N1)pdm09 vaccine was effective in preventing 55–60% of influenza and pneumonia hospitalizations among children and younger adults. Although less effective among ≥65 adults(~10%), the vaccine benefited this group the most as measured by the number-needed-to-vaccinate.