Three Cochrane Reviews focusing on the prevention of influenza in healthy adults, healthy children, and in the elderly are long-running reviews under the same senior author team.
Over the years the reviews have progressively accumulated evidence leading to ever greater stability in their conclusions. ‘Stable’ is a publication flag that usually indicates that the results are unlikely to change with the inclusion of new studies, such is the certainty of the results.
We have reached a point where the evidence is not showing anything different to what it has done for a number of years. We know with varying degrees of certainty about vaccination effects on influenza and ILI [influenza-like-illness], but the gap in our understanding of how vaccines affect the consequences of influenza persist.
The three reviews will not be updated again unless certain criteria are met.
First, a new trial that meets inclusion criteria becomes available. Few trials of interest have been conducted recently, as a comparison with an inactive control is considered by some to be unethical. In the elderly, the latest completed trial dates from nearly two decades ago. Our searches have failed to find relevant ongoing trials.
A second condition is the introduction of a new generation of vaccines, based on new technology.
The third condition is more complex: the development and testing of a new causal paradigm for ILI and influenza.
[T]he vaccination selection and production programmes are based on aetiological assumptions…
Overall the largest dataset to have accumulated to date is from trials conducted in the population least likely to benefit from vaccines but most likely to produce immunity : healthy adults.
In healthy adult trials a high serological response is matched by a very small clinical effect (71 healthy adults need to be vaccinated to prevent one of them experiencing influenza). This weak effect cannot be explained simply by the mismatch of vaccine antigens with wild virus ones.
There is little evidence on prevention of complications, transmission, or time off work.
Observational studies were included in the reviews over a decade ago in the hope they could provide long-term and rare harms data and improve the external validity of the trial evidence.
They turned out to be of such low quality that their conclusions were inconclusive or unreliable.
The underlying assumption that influenza vaccination does not affect the risk of non-influenza is contradicted by a recent report from the follow up of a trial by Cowling et al.
In 115 participants, those who received trivalent influenza vaccines had higher risk of acute respiratory infection associated with confirmed non-influenza respiratory virus infection compared to placebo recipients.
Current yearly registration of candidate influenza vaccines is based on their ability to trigger a good antibody response. But antibody responses are poor predictors of field protection.
This is another example of the use of surrogate outcomes in biomedicine, where effects on clinically important outcomes remain unmeasured or unproven from randomised trials…
However there is no reliable system to monitor and quantify the epidemiology and impact of ILI [influenza-like-illness], the syndrome that presents clinically. Few states produce reliable data on the number of physician contacts or hospitalised cases due to ILI, and none tie these data to the proportion of ILI caused by influenza. We do not know for certain what the impact of ILI is, nor the impact of the
proportion of ILI caused by influenza.
The standard quoted figure of 36,000 yearly deaths in the US is based on the “respiratory and circulatory deaths” category including all types of pneumonia, including secondary to meconium ingestion or bacterial causes.
When actual death certificates are tallied, influenza deaths on average are little more than 1,000 yearly.
So the actual threat is unknown (but likely to be small) and so is the estimation of the impact of vaccination.
[O]ur reviews will remain as a testimonial to the scientific failure of industry and governments to address the most important clinical outcomes for patients.