Pre-existing national health registries created for surveillance purposes allowed us to estimate VE and describe vaccine failures during the 2009-2010 influenza pandemic. Our results show that vaccination with an AS03-adjuvanted monovalent vaccine against A(H1N1)2009 conferred a very high protective effectiveness against laboratory confirmed pandemic influenza in Norway, regardless of immunity threshold chosen.
We measured VE by week in order to take account of the changes in the denominators over time as when more people were vaccinated. An overall calculation with fixed denominators would have yielded VE of 99% and 97% with 15 and eight days immunity thresholds, respectively. This underlines that, in specific scenarios, such as a pandemic situation where a vaccine is not distributed simultaneously to the whole population, VE should always be estimated taking into account time in order to avoid an overestimated measurement of the protection provided by the vaccine. Controlling by time has already shown to be useful when estimating VE in the pandemic in other published studies . Together with time, age is a critical factor when determining VE. However, due to the low number of influenza cases notified per week in each age-group, we were not able to adjust our VE estimates by age.
There are some intrinsic characteristics of the national health registries used in our study that should be taken into account when interpreting our results. MSIS does not include all pandemic influenza cases that occurred in Norway, since at the time when the vaccination campaign began, mainly persons with severe ILI symptoms or those that belonged to a risk group were sampled. This means that the laboratory-confirmed cases notified in MSIS are not a random sample of all the cases occurring in the Norwegian population. If the likelihood of having laboratory-confirmed influenza and thus be notified to MSIS, was associated with vaccination status, our VE estimate could be biased. It should also be noted that not all vaccinations were notified to SYSVAK. Overall, the number of vaccinated population shown in Table 1 and Table 2 is expected to be around 10% higher, leading to an even lower incidence among those vaccinated. With other factors being equal, this effect alone will have led to an underestimation of the VE.
This study is also subject to other potential biases. Firstly, at the beginning of the pandemic period only groups at risk were recommended to be vaccinated. Patients with underlying conditions, like immunity disorders, may have had a lower response to the vaccine. This would result in an underestimation of the VE. This bias is known as confounding by indication. Our results may reflect this, since the proportion of vaccine failures during the first weeks after the vaccination campaign started is the highest during the whole period.
Secondly, the opposite effect, an overestimation of VE can be seen if healthy people were more likely to be vaccinated. This situation is known as healthy vaccinee confounding and may have occurred in the period when vaccination was recommended to the general population and most of the people in the risk groups had already been vaccinated. There are some indications of this bias in our results since the VE estimate improved as the vaccination campaign moved on.
Thirdly, clinicians may have been less likely to test for influenza in patients known to be vaccinated, thinking that influenza was an unlikely cause of their symptoms. Due to this potential diagnostic bias, vaccine failures may have been missed and VE overestimated. However, the NIPH encouraged clinicians to document suspected vaccine failures by testing in order to minimize this bias.
Finally, as the campaign developed, more and more persons were immune due to vaccination or natural immunity following infection. This probably led to some degree of herd protection, which may also have had an effect on the measured VE.
Our results are in concordance with findings of published meta-analyses of randomized trials of influenza vaccines [11, 12]. They are also consistent with the conclusions of previous pandemic influenza VE studies conducted in other European countries [9, 13–16] and Canada , where it was concluded that, overall, the pandemic influenza vaccine was highly effective in preventing laboratory-confirmed infection with pandemic influenza A(H1N1)pdm09. Our study also supports findings in of previous preliminary studies conducted in Norway during the pandemic period .
Regardless the high VE measured, our results highlight specific age groups that seemed to be less protected by the vaccine and in need of more time to develop immunity. Special attention should be paid to those less than 10 years of age due to high number of people involved. However, in order to be able to recommend specific precautions after vaccination in this age group, further studies controlling for potential confounding factors (like underlying diseases) should be carried out. The nature of our study, using already available register based information, did not allow us to control for such factors.
We used two existing registries for this study. MSIS, the infectious disease register, was augmented during the pandemic by inclusion of laboratory-confirmed influenza A(H1N1)pdm09 as notifiable disease on a case based level. This mainly served surveillance purposes and for informing the public health response, but the data could also be used for evaluation of the interventions put in place, as shown in this study. The cost of the augmentation was small as already existing procedures and infrastructure was used. SYSVAK, the immunisation register, was augmented by including pandemic vaccination. The purpose of this was both to monitor the execution of the vaccination campaign and to prepare for follow-up studies. A web-based platform was introduced and linked to the national population register to facilitate easy entry of each vaccination by the vaccinators. The time needed for entry of one vaccination was less than 30 seconds. Because of the high number of vaccinations, however, the total time spent on registrations was considerable.