Flu jab is not a 'waste of time'

Crabsallover comment: As the Public Health England Press Release says 'The research, based on the results from 1,314 patients presenting in primary care across the UK, found that vaccine effectiveness in preventing laboratory confirmed influenza was estimated to be 3% overall. This compares to approximately 50% vaccine effectiveness that has typically been seen in the UK over recent years.'

PHE also says" In the UK, influenza A(H3N2) is the predominant subtype circulating this season to date, and H3N2 viruses similar to A/Texas/50/2012 are the strains that the vaccine currently protects against. Analysis conducted by PHE has shown a large proportion of flu viruses circulating have shown evidence of either antigenic or genetic drift from A/Texas/50/2012, and were similar to another H3N2 strain; A/Switzerland/9715293/2013. The A/Switzerland/9715293/2013 strain has been recommended for inclusion in the southern hemisphere influenza vaccine to be used in 2015.'

source: http://en.wikipedia.org/wiki/File:InfluenzaNomenclatureDiagram.svg

and
'The World Health Organization monitors influenza globally and each year recommends the strains of flu virus that should be included in the flu vaccine for the forthcoming flu season. It takes from February through to August / September to produce sufficient quantities of the flu vaccine. If a change in the virus is detected once production has started it is not possible to change it.  Throughout the last decade, there has generally been a good match between the strains of flu in the vaccine and those that subsequently circulate, so it’s crucial that these results do not discourage people in at-risk groups from having flu vaccination now, or in the future.'

Interesting comparison of what is in seasonal H3N2 flu vaccines.

Friday February 6 2015

This year’s flu jab may still protect against other strains

“Flu jab given to millions is 'useless',” and "Flu jab is a waste of time," are the irresponsible headlines in The Daily Telegraph and the Daily Mail.

While recent research shows that the currentseasonal flu vaccine only has 3% protection against the main circulating strain – A(H3N2) – in adults, it can still protect against other strains.

Both papers also ignore the fact that another version of the flu vaccine, in the form of a nasal spray designed forvulnerable children, is also available.

Discouraging parents of vulnerable children from getting vaccinated could increase the risk of serious childhood illnesses and possible hospitalisation.

Why is the flu vaccine not working?

There are many strains of the influenza virus and each one can mutate. It takes time to develop and produce vaccines against them. Global surveillance is used to predict which strains are likely to be circulating the following winter, and in February the World Health Organization (WHO) announces which strains the flu vaccine should cover. Last year, it decided to cover three flu varieties:

• Influenza A (H1N1), also known as “swine flu"
• Influenza A (H3N2)
• Influenza B

In March, the WHO Global Influenza Surveillance and Response System detected a new strain of influenza A (H3N2), but this was too late to change the production of the vaccine.

It was also not known whether this particular strain would be the predominant strain this winter, which it has been, and so the vaccine is not effective against it.

‘A Jack Bauer car chase’

“Trying to predict which seasonal flu vaccine to produce each year must be a bit like a Jack Bauer [hero of the TV thriller series '24'] car chase in Los Angeles.

“At any intersection, the fugitive has three choices of direction. Bauer can’t catch up, and he doesn’t know the ultimate destination, so he has to try to guess the likeliest turns, and place his limited team in side streets where they’re most likely to block the fugitive, to slow him down or capture him. Even with Jack Bauer’s experience, this is bound to prove somewhat hit and miss.”

Dr Michael Skinner, Reader in Virology, Imperial College London (and fan of ‘24’).

How effective is it?

The vaccine is effective against the other strains of influenza, but not the new strain of influenza A (H3N2). The mid-season vaccine effectiveness rate is just 3.4%. Vaccination against this new strain and other possible mutations will be considered at the WHO meeting this February for next winter.

Reactions to the news

Dr Michael Skinner, Reader in Virology, Imperial College London said: “The current type of seasonal influenza vaccine is, at the moment, the best we have. Annually it saves tens of thousands of lives. Unusually, but not uniquely, this year one (H3N2) of the four targeted viruses ‘drifted’ (mutated) in an unanticipated direction after the vaccine was formulated for production, so that the vaccine offers little protection against the drifted H3N2.

"Even so, the vaccine still protects against the other three components (pre- and post-2009 H1N1 and B). And it does at least stop the virus drifting back along the path that had been predicted. To describe it as ‘useless’ would be misguided.”

Should you still get the jab?

The other strains can still cause infection so the vaccine is still recommended for pregnant women, people aged over 65 and those with any of the following conditions:

• chronic (long-term) respiratory disease, such as asthma (that requires inhaled or tablet steroid treatment or has led to hospital admission in the past), chronic obstructive pulmonary disease (COPD) or bronchitis 
• chronic heart disease, such as heart failure 
• chronic kidney disease 
• chronic liver disease, such as hepatitis 
• chronic neurological conditions, such as Parkinson's diseaseor motor neurone disease 
• diabetes
• problems with your spleen – for example, sickle cell disease, or if you have had your spleen removed 
• a weakened immune system due to conditions such as HIV and AIDS, or as a result of medication such as steroid tablets orchemotherapy

When to visit your GP

If you are otherwise fit and healthy, there is usually no need to visit your GP if you have flu-like symptoms.

The best remedy is to rest at home, keep warm and drink plenty of water to avoid dehydration.

You can take paracetamol or ibuprofen to lower a high temperature and relieve aches.

If you are in any of the high risk groups listed above then you should visit your GP.

Depending on your circumstances, your GP may recommend a short course of antiviral medication, such as Tamiflu (oseltamivir). 

Antivirals are not used for everyone with flu because this would lead to further mutations in the viruses and drug resistance, making them ineffective.

If you suspect you have the flu it is important to take steps to prevent it spreading; especially to one or more of the vulnerable groups listed above.

Always:

• make sure you wash your hands regularly with soap and water
• clean surfaces such as your keyboard, telephone and door handles regularly to get rid of germs
• use tissues to cover your mouth and nose when you cough or sneeze
• put used tissues in a bin as soon as possible

Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on Twitter. Join the Healthy Evidence forum.

Analysis by 

Edited by NHS Choices

Links to the headlines

Flu jab given to millions is 'useless'. The Daily Telegraph, February 6 2015

Flu jab is a waste of time for 97% of patients: Vaccine developed only a year ago no longer 'matches' because the virus has mutated so much. Daily Mail, February 6 2015

Flu vaccine 'barely effective' against main viral strain. BBC News, February 5 2015

Useless flu jab blamed for surge in death toll. Daily Express, February 6 2015

Current winter flu jab works in only 3% of cases. ITV News, February 6 2015

Flu vaccine gives only ‘low protection’ in UK this winter, experts warn. The Guardian, February 5 2015

Flu jab given to millions offers almost no protection. The Times, February 6 2015

Flu Jab Found To Work In Just 3% Of Cases. Sky News, February 6 2015

Links to the science

Pebody RG, Warburton F, Ellis J, et al. Low effectiveness of seasonal influenza vaccine in preventing laboratory-confirmed influenza in primary care in the United Kingdom: 2014/15 mid-season results. Eurosurveillance. Published online February 5 2014

Further reading

Public Health England. Flu vaccine shows low effectiveness against the main circulating strain seen so far this season – Press Release. February 5 2015

reposted (unedited) from: http://www.nhs.uk/news/2015/02February/Pages/Flu-jab-is-not-a-waste-of-time.aspx

crabsallover highlights, key points, comments / links.

Tamiflu and Relenza - confidential trials reveal no significant benefit - Cochrane Research

reposted from: http://www.nhs.uk/news/2014/04April/Pages/questions-over-tamiflu-relenza-effectiveness.aspx

crabsallover highlights, key points, comments / links.

Links to the science

Jefferson T, Jones MA, Doshi P, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database of Systematic Review. Published online April 10 2014

Further reading

What the Tamiflu saga tells us about drug trials and big pharma. Bed Goldacre, The Guardian, April 10 2014

Tamiflu in BMJ 2003 to 2012 timeline

reposted from: BMJ Timeline

crabsallover highlights, key points, comments / links.


Tamiflu in the BMJ: This interactive timeline shows articles about Tamiflu which were published in the BMJ, between 2003 and 2012.

A review of unpublished regulatory information from trials of neuraminidase inhibitors (Tamiflu - oseltamivir and Relenza - zanamivir) for influenza

reposted from: Cochrane Summaries
Jefferson T, Jones MA, Doshi P, Del Mar CB, Heneghan CJ, Hama R, Thompson MJ. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database of Systematic Reviews 2012, Issue 1. Art. No.: CD008965. DOI: 10.1002/14651858.CD008965.pub3

crabsallover highlights, key points, comments / links.

Jefferson T, Jones MA, Doshi P, Del Mar CB, Heneghan CJ, Hama R, Thompson MJ

Published Online: 

October 17, 2012

We decided to update and amalgamate our reviews on the antiviral drugs zanamivir and oseltamivir for influenza on the basis of the manufacturers' reports to regulators (called clinical study reports) and regulators' comments (which we called regulatory information). Clinical study reports are extensive documents with exhaustive details of the trial protocol, methods and results. In view of the unresolved discrepancies in the data presented in published trial reports and of the substantial risk publication bias in this area, we elected not to use data from journal articles. Availability of documents generated by national and regional regulatory bodies during licensing processes in the UK, USA, continental Europe and Japan, partial trial reports from the manufacturers of oseltamivir and from the European regulator European Medicines Agency (EMA), enabled us to verify information from the trials. The authors have been unable to obtain the full set of clinical study reports or obtain verification of data from the manufacturer of oseltamivir (Roche) despite five requests between June 2010 and February 2011. No substantial comments were made by Roche on the protocol of our Cochrane Review which has been publicly available since December 2010. Based on our assessments of the documents we could obtain, we came to the conclusion that there were substantial problems with the design, conduct and availability of information from many of the trials. Due to these concerns we decided not to proceed with a meta-analysis of all the oseltamivir data as we had intended. Instead we carried out analyses of effects on symptoms (shortens them by 21 hours or so) and hospitalisations (no evidence of effect) of people with influenza-like illness ('flu') on data from all the people enrolled in treatment trials of oseltamivir. Other outcomes could not be assessed due to unavailability of data for all the people enrolled in treatment trials of oseltamivir.  Our independent analysis concurs with the conservative conclusions regarding the effects of both drugs by the US Food and Drug Administration (FDA). The FDA only allowed claims of effectiveness of both drugs for the prevention and treatment of symptoms of influenza and not on other effects (such as interruption of person-to-person spread of the influenza virus or prevention of pneumonia). There is evidence to suggest that both drugs are associated with harms (oseltamivir: nausea, vomiting; zanamivir: probably asthma). The FDA described the overall performance of both drugs as "modest". We expect full clinical study reports containing study protocol, reporting analysis plan, statistical analysis plan and individual patient data to clarify outstanding issues. These full clinical study reports are at present unavailable to us.

HideAbstract (click to read)

Background: 

Planning for outbreaks of influenza is a high priority public health issue for national governments. Neuraminidase inhibitors (NIs) are thought to help reduce the symptoms of influenza with several possible mechanisms proposed. NIs have been stockpiled with a view to their widespread use in the event of a pandemic. However, the evidence base for this class of agents remains a source of debate. In a previous review we have documented substantial risks of publication bias of trials of NIs for influenza (60% of patient data from phase III treatment trials of oseltamivir have never been published) and reporting bias in the published trials. Our confidence in the conclusions of previous versions of this review has been subsequently undermined. Since we have become aware of a large number of unpublished trials of NIs in the management of influenza, this review updates and merges existing reviews in this area.

Objectives: 

To review clinical study reports of placebo-controlled randomised trials, regulatory comments and reviews ('regulatory information') of the effects of the NIs oseltamivir and zanamivir for influenza in all age groups and appraise trial programmes, rather than single studies.

Clinical study reports are very detailed, unpublished clinical trial data containing in-depth descriptions of protocol rationale, methodsanalysis plans, trial results and organisational documents (such as contracts). A series of clinical studies designed and conducted by one sponsor represents a trial programme of a drug indication (for example treatment of influenza).

Search strategy: 

We searched trial registries, cross-referencing published and unpublished sources and corresponded with manufacturers and regulators. We searched the archives of the US Food and Drug Administration (FDA) and European and Japanese regulators. The evidence in this review reflects searches to obtain relevant information up to 12 April 2011.

Selection criteria: 

We included regulatory information based on assessments of randomised controlled trials (RCTs) conducted in people of any age who had either confirmed or suspected influenza, or who had been exposed to influenza in the local community or place of residence. We included information which had been made available by our deadline.

Data collection and analysis: 

We indexed regulatory information in two purpose-built instruments and reconstructed trials using CONSORT statement-based templates. To progress to Stage 2 (full analysis) we sought manufacturer explanations of discrepancies in the data. GlaxoSmithKline (GSK) offered us individual patient data and responded to our queries, but Roche did not provide us with complete clinical studyreports. In Stage 2 we intended to analyse trials with validated data (i.e. assuming our validation questions aimed at clarifying omissions and discrepancies were resolved). No studies progressed to Stage 2. We carried out analyses of the effects of oseltamivir on time to first alleviation of symptoms and hospitalisations using the intention-to-treat (ITT) population and tested five hypotheses generated post-protocol publication.

Main results: 

We included and analysed data from 25 studies (15 oseltamivir and 10 zanamivir studies). We could not use data from a further 42 studies due to insufficient information or unresolved discrepancies in their data. The included trials were predominantly conducted in adults during influenza seasons in both hemispheres. A small number of studies were conducted in older people residing in care homes and in people with underlying respiratory diseases. The studies had adequate randomisation and blinding procedures, but imbalances in the analysis populations available (ITT influenza-infected) left many of the studies at risk of attrition bias. All the studies were sponsored by manufacturers of NIs. Time to first alleviation of symptoms in people with influenza-like illness symptoms (i.e. ITTpopulation) was a median of 160 hours (range 125 to 192 hours) in the placebo groups and oseltamivir shortened this by around 21 hours (95% confidence interval (CI) -29.5 to -12.9 hours, P < 0.001; five studies) but there was no evidence of effect on hospitalisations based on seven studies with a median placebo group event rate of 0.84% (range 0% to 11%): odds ratio (OR) 0.95; 95% CI 0.57 to 1.61, P = 0.86). These results are based on the comprehensive ITT population data and are unlikely to be biased. A post-protocol analysis showed that participants randomised to oseltamivir in treatment trials had a reduced odds being diagnosed with influenza (OR 0.83; 95% CI 0.73 to 0.94, P = 0.003; eight studies), probably due to an altered antibody response. Zanamivir trials showed no evidence of this. Due to limitations in the design, conduct and reporting of the trial programme, the data available to us lacked sufficient detail to credibly assess a possible effect of oseltamivir on complications and viral transmission. We postponedanalysis of zanamivir evidence because of the offer of individual patient data (IPD) from its manufacturer. The authors have been unable to obtain the full set of clinical study reports or obtain verification of data from the manufacturer of oseltamivir (Roche) despite five requests between June 2010 and February 2011. No substantial comments were made by Roche on the protocol of our Cochrane Review which has been publicly available since December 2010.

Authors' conclusions: 

We found a high risk of publication and reporting biases in the trial programme of oseltamivir. Sub-population analyses of the influenza infected population in the oseltamivir trial programme are not possible because the two arms are non-comparable due to oseltamivir's apparent interference with antibody production. The evidence supports a direct oseltamivir mechanism of action on symptoms but we are unable to draw conclusions about its effect on complications or transmission. We expect full clinical studyreports containing study protocol, reporting analysis plan, statistical analysis plan and individual patient data to clarify outstanding issues. These full clinical study reports are at present unavailable to us.