Australia. Trivalent flu shots suspended after kids hospitalised, fatality

[SusanC]

Re: Australia. Trivalent flu shots suspended after kids hospitalised, fatality

Contrast:


Influenza Vaccines: Pre-approval studies for use in children aged 6 months to 3 years

Focetria ? (H1N1 with adjuvant MF 59; manufacturer: Novartis, Europe)


versus


Fluvax ? junior (trivalent, without adjuvant, manufacturer: CSL Limited, Australia)




Fever (≥38?C) as a systemic adverse event:


Focetria ? (H1N1, adjuvanted): 14 %

Fluvax ? junior (trivalent, including H1N1; not adjuvanted): 22.5 %

Even though 22.5% seems high for a flu vaccine and deserves attention, I would caution against such head-to-head comparisons, not least because these are not matched groups (eg neither subject selection nor criteria nor method of follow-up are matched), plus the antigen contents are different. One is monovalent in low dose but with adjuvant, the other is trivalent in a new combination, ie different from previous years. The comparison may not tell us much.

 

[german-docter]

Re: Australia. Trivalent flu shots suspended after kids hospitalised, fatality

Even though 22.5% seems high for a flu vaccine and deserves attention, I would caution against such head-to-head comparisons, not least because these are not matched groups (eg neither subject selection nor criteria nor method of follow-up are matched), plus the antigen contents are different. One is monovalent in low dose but with adjuvant, the other is trivalent in a new combination, ie different from previous years. The comparison may not tell us much.

SusanC :tiphat:

I'd like to agree to some of your limitations. Indeed, it's not the same stuff and head-to-head comparison may be improper that way.

Subject-selection and method of follow-up do not seem to be different (for both vaccine approval studies: healthy children >/= 6 months to < 36 months of age, temperature >/= 38.0°C within the first week after the administration of the vaccine).

Regarding the H1N1 component of the vaccines, the strain used for the antigen is the same (A/California/7/2009 (NYMC X-181)) and the dose of the H1N1 component is the same either (7.5µg HA).

Different is the use of an adjuvant (Focetria only) and the monovalent versus trivalent matter (Fluvax junior additionally containing H3N2-influenza A and influenza B-components with 7.5µg HA each).

CSL's pandemic H1N1-vaccine Panvax (R) junior, which contains the same H1N1-component as Fluvax (R) junior had been studied in young children 6 months to <3 years before and fever also occured in 21.4 % (n = 103).

Quote: " The most common solicited systemic adverse reactions for the younger age group (Group A) were irritability, diarrhoea and fever".

Source: see table 4 page 6 at:
Product Information: Panvax® H1N1 Vaccine / Panvax® H1N1 Vaccine Junior
(AUST R 165345, 163897, 163900 and 166312)
5mL and 10mL multi-dose vial; 0.5mL and 0.25mL pre-filled
single dose syringe presentations (December 2009):
http://www.emergency.health.nsw.gov...f/h1n1_vaccine_product_information_031209.pdf​

Thus the contrast between Focetria and Panvax junior (Fluvax junior, respectively) regarding fever also may reflect some differences in the manufacturing process. And this is the reason for posting the difference in the light of the "residual RNA"-hypothesis from Professor Nikolai Petrovsky and his colleages (post #57 + 58).

As I said before, looking at the pre-approval studies, IMO a high rate of fever in young children (6 months to <3 years) following the influenza vaccination is not unusual and the higher rate of febrile convulsions also should have not be too surprising to the Australian vaccination experts group (ATAGI) and the Therapeutic Goods Administation (TGA). em

 

[Giuseppe]

Re: Australia. Trivalent flu shots suspended after kids hospitalised, fatality

Western Australia reviews flu vaccine program (ABC News (Australian Broadcasting Corporation, edited)

[Source: ABC, <cite cite="http://www.abc.net.au/news/stories/2010/05/04/2890191.htm">WA reviews flu vaccine program - ABC News (Australian Broadcasting Corporation)</cite>. May 4, 2010, edited.]

WA reviews flu vaccine program


The West Australian Government is reviewing the state's handling of the flu vaccine program.

Last month WA was the first state to suspend its influenza vaccine program for children under five after hundreds of cases of adverse reactions, including fever, vomiting and convulsions.

The program was suspended nationally the next day after children in other states and territories reported severe side-effects.

The WA Health Minister Kim Hames says the review will recommend ways the department can improve its reporting systems to pick up public health risks earlier.

"What the enquires looks at is the response time of the West Australian health department," he said.

"Did we do a good job or not? Did we do everything we could have?".

At the weekend health consumers demanded answers from health authorities to restore confidence in vaccination.

The Therapeutic Good Administration has tested batches of vaccine from WA and found there was nothing abnormal about them.

Maxine Drake from the WA Health Consumers Council said the lack of information could permanently deter some parents from vaccinating their children.
-
-----

 

[german-docter]

Re: Australia. Trivalent flu shots suspended after kids hospitalised, fatality

Correction (regarding posts #59 and 62) for clarification:

The Fluvax junior (CSLCT-FLU-04-05) – study with n = 151 (young children >/= 6 months to <3yr) and 22.5 percent fever is a 2004 – 2005 study without the H1N1 component used for Fluvax junior 2010 vaccine formulation

The only adverse event data published regarding the H1N1 component of the Fluvax junior 2010 vaccine formulation do solely come from the 2009 Panvax junior pre-approval study anyway (n = 103 for young children 6 months to < 3 yr): 21.4 percent fever.

Nobody ever has conducted a pre-approval study with the real Fluvax junior 2010 formulation in order to determine the rate of adverse events that will occur with the new combination of the seasonal influenza vaccine and the pandemic H1N1 vaccine.

Flu vaccine 'reveals no abnormalities'
(...)

Each year, CSL's Fluvax vaccine contains fragments of three different types of influenza virus as recommended by the Therapeutic Goods Administration (TGA).

The 2010 version includes the swine flu strain H1N1.

The last paediatric study of Fluvax occurred in 2004-05 but "quality testing" is conducted every year, CSL said.

A trial of the separate swine flu vaccine for children was conducted in 2009.
(...)

http://news.smh.com.au/breaking-new...e-reveals-no-abnormalities-20100430-tz30.html

Let’s review the data:

Panvax® H1N1 Vaccine / Panvax® H1N1 Vaccine Junior(AUST R 165345, 163897, 163900 and 166312)Product Information December 2009
http://www.emergency.health.nsw.gov...f/h1n1_vaccine_product_information_031209.pdf

Fluvax® Junior vaccine 2010 (AUST R 149127) Fluvax® Junior For season 2010 Product Information November 2009
http://secure.healthlinks.net.au/content/csl/pi.cfm?product=cspfluvj11109

Fluvax® Junior vaccine 2010
http://secure.healthlinks.net.au/content/csl/pi.cfm?product=cspfluvj11109
(..)
Clinical trials:
Paediatric study (CSLCT-FLU-04-05)
The safety, tolerability and immunogenicity of Fluvax® vaccine in a paediatric population (≥ 6 months to < 3 years and ≥ 3 years to < 9 years) were demonstrated in an open label, multi-centre study (CSLCT-FLU-04-05). Participants who had not been previously vaccinated against influenza were stratified and vaccinated according to age: Group A: ≥ 6 months to < 3 years received two 0.25 mL doses and Group B: ≥ 3 years to < 9 years received two 0.5 mL doses. The total number of participants was 298 (Group A n=151; Group B n=147). There were no reports of serious adverse events related to Fluvax® vaccine during the vaccination period. Table 1 presents the proportion of participants with solicited adverse events within 7 days after administration of Fluvax® vaccine. The table includes all adverse experiences reported with an incidence of 2% or greater. A dash represents an incidence of less than 2%. Unsolicited adverse events were collected for 30 days post-vaccination. Very common unsolicited events (≥ 1/10) reported were rhinitis, cough, teething and influenza-like illness.
Table 1: Proportion of Paediatric Subjects with Solicited Local and Systemic Adverse Events within 7 days of Administration of Fluvax® vaccine

Group A (n = 151)(≥ 6 months to < 3 years)
Solicited Adverse Event - dose 1 - dose 2
Fever* - 22.5 % - 22.5 “

Post-marketing surveillance:
The following adverse experiences have been spontaneously reported during post-approval use of Fluvax®vaccine/Fluvax® Junior vaccine. The adverse events reported below are presented according to System Organ Class and frequency. This data reflects experience in children and adults. Adverse event frequencies are defined as follows: Very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000) and very rare (< 1/10,000).
(…)
General Disorders and Administration Site Conditions
Very Common: Injection site inflammation.
Common: Influenza-like illness.
Injection site ecchymosis and induration.
Influenza-like illness may include pyrexia, chills, headache, malaise and myalgia.​

The Fluvax (CSLCT-FLU-04-05) – study with n = 151 (young children >/= 6 months to <3yr) and 22.5 percent fever is a 2004 – 2005 study without the H1N1 component used for Fluvax junior 2010 vaccine formulation





CSL's pandemic H1N1-vaccine Panvax (R) junior, which contains the same H1N1-component as Fluvax (R) junior had been studied in young children 6 months to <3 years before and fever occured in 21.4 % (n = 103).

" The most common solicited systemic adverse reactions for the younger age group (Group A) were irritability, diarrhoea and fever".
Source: see table 4 page 6 at:
Product Information: Panvax® H1N1 Vaccine / Panvax® H1N1 Vaccine Junior
(AUST R 165345, 163897, 163900 and 166312)
5mL and 10mL multi-dose vial; 0.5mL and 0.25mL pre-filled
single dose syringe presentations (December 2009):
http://www.emergency.health.nsw.gov...f/h1n1_vaccine_product_information_031209.pdf​

...
Product information of Panvax junior Dec. 2009 (page 6):

Post-marketing surveillance:
Post-marketing data for Panvax® H1N1 vaccine are limited and have not identified any new safety concerns. It is anticipated that the adverse events after vaccination will be similar to those spontaneously reported during post-approval use of CSL’sseasonal influenza vaccine, Fluvax® vaccine. The adverse events reported are presented below according to System Organ Class and frequency. These data reflect experience in children and adults with Fluvax® vaccine ...​

[comment: i.e. Fluvax vaccine prior to 2010 and without the H1N1 component !].

...
Adverse event frequencies are defined as follows:
Very common ( ≥ 1/10 ), common ( ≥ 1/100 and < 1/10 ), uncommon ( ≥ 1/1000 and < 1/100 ), rare ( ≥ 1/10 000 and < 1/1000 ) and very rare ( < 1/10 000).
General Disorders and Administration Site Conditions
These reactions usually resolve within 1-2 days without treatment.
Very common: Injection site inflammation
Influenza-like illness (for thiomersal-containing vaccine only)
Common: Injection site ecchymosis and induration
Influenza-like illness (for thiomersal-free vaccine only)Influenza-like illness may include pyrexia, chills, headache, malaise and myalgia.​

Thus, the only adverse event data published regarding the H1N1 component of the Fluvax junior 2010 vaccine formulation do solely come from the 2009 Panvax junior pre-approval study anyway (n = 103 for young children 6 months to < 3 yr): 21.4 percent fever.

Conclusion: Nobody ever has conducted a pre-approval study with the real and actually used Fluvax junior 2010 formulation in order to determine the rate of adverse events that will occur with the new combination of the seasonal influenza vaccine and the pandemic H1N1 vaccine.

 

[german-docter]

Re: Australia. Trivalent flu shots suspended after kids hospitalised, fatality

Comparison must be read this way:

Influenza Vaccines:
Pre-approval studies for use in children aged 6 months to 3 years

Fever (≥38?C) as a systemic adverse event:

Focetria ? (monovalent H1N1, MF 59 adjuvanted, Novartis): 14 %

Fluvax ? junior 2004-2005 (trivalent, EX-cluding H1N1; not adjuvanted, CSL): 22.5 %

Panvax ? junior 2009 (monovalent H1N1, not adjuvanted, CSL): 21.4 %

Fluvax ? junior 2010 (trivalent, for the first time including H1N1, not adjuvanted, CSL): ?n fact unknown
(Quote: ?it is anticipated that it will be similar to ? [Fluvax? junior 2004-2005 vaccine]?)

 

[tetano]

Re: Australia. Trivalent flu shots suspended after kids hospitalised, fatality

Qld Health reports 150 cases of flu reactions


Queensland Health (QH) says it has referred almost 150 cases of possible adverse reactions from flu vaccinations to the Therapeutic Goods Administration (TGA).

Seasonal flu vaccines for children under five remain suspended while further tests are carried out.

It follows a spike in adverse reactions across the country.

QH chief medical officer Dr Jeannette Young has told the ABC 1 Stateline Queensland program authorities have received 196 reports in total, but not all are serious.

"We'd not received many reports when this first came to light so I did go out a number of times and ask GPs and vaccine providers to please let us know of any incidents so that we could look into them," she said.

"So that we can see if there's anything unusual going on.

"We've received significant numbers of reports from those people now."

A report is also being prepared for the Coroner into last month's death of a Brisbane child who had had a flu shot the day before.


http://www.abc.net.au/news/stories/2010/05/07/2893518.htm

 

[german-docter]

Re: Australia. Trivalent flu shots suspended after kids hospitalised, fatality

http://www.bmj.com/cgi/eletters/340/may04_2/c2419


Australia suspends seasonal flu vaccination of young children
BMJ.2010; 340: c2419

Adverse events following influenza vaccination in Australia--should we be surprised?

Peter Collignon, Peter Doshi, Tom Jefferson (7 May 2010)

There have been large numbers of major adverse reactions to this year's seasonal influenza vaccine in Australia, and the vaccine has been suspended for use in children aged five and under [1,2]. These reactions have occurred across the country and involved multiple batches of vaccine [2]. In the state of Western Australia where the problem was first detected, reports suggest that of the 20,000 to 30,000 children vaccinated, more than 250 had adverse reactions and 55 had febrile convulsions before vaccination was suspended in young children [2]. Assuming all convulsions were in children, about one child in every 500 vaccinated had a febrile convulsion. Across Australia, media accounts indicate that more than 400 adverse reactions [3] including 77 cases of febrile convulsion [1] have been reported by regulators. While attention remains focused on reactions in very young children, reports suggest only one-third of the reactions may have occurred in children under five [4].

Although this situation has triggered considerable controversy in Australia, the story has attracted little to no media attention in the US and Europe. Similarly, the media has paid little attention to a US H1N1 federal vaccine safety advisory committee which recently reported detecting signals for Guillain-Barre syndrome (GBS), Bell's palsy, and thrombocytopenia in the monovalent H1N1 (swine flu) vaccine [5]. The same monovalent H1N1 antigen component under review in the US is scheduled to be added to the US trivalent seasonal vaccine and is contained in the Australian trivalent seasonal vaccine and will be given to children, pregnant women and adults [6].

Data from a previous Australian study of H1N1 vaccine show that a large percentage of children developed fevers following vaccination--in children less than 3 years, between three and six in every ten vaccinated, depending on dose [7,8]. The data also show a dose response effect -- the larger the vaccine dose, the more severe the harms. There was also an age relationship: children under the age of three developed fevers at more than twice the rate of older children [7,8]. The study was however underpowered to detect febrile convulsions at the current rates in Australia, with only 162 children below the age of three. The size problem was further aggravated by stratification by age group and antigen dose.

Presumably the vaccine manufacturer CSL, which sponsored the trial, and Australia?s regulatory body, the Therapeutic Goods Administration (TGA), which used this data in approving the vaccine for children, were aware of these important findings. But authors of the study published earlier this year did not discuss the high incidence of fever associated with vaccination [7]; data were instead only reported in online-only supplementary tables [8].

Overall, the percentages of children under three who developed a fever after vaccination appear very high; thirty five per cent with the 15 ug dose and 62% after a 30 ug dose [7,8]. Of those that received a 7.5 ug dose in the seasonal influenza vaccine, 23% develop a fever of >38 degrees Celsius [6].

The large number of children suffering harms--and subsequent suspension of the vaccine--challenges the assumption that regulators are ensuring the safety and efficacy of all marketed therapeutics. Should we be surprised that these problems have occurred with influenza vaccine, a vaccine used for over 60 years, said to have "an established record of safety in all age groups"? [9] There are actually relatively little data on the effects of vaccinating young children against influenza [10]. Some manufacturers have even withheld data from public scrutiny amidst general indifference [10,11]. Evidence from all comparative influenza vaccine studies shows that harms, when they are investigated, are not reported consistently and systematically [10,11]. As pandemic vaccines are provided to governments and not individuals and manufacturers are indemnified for damages caused to users [12-14], there seem to be few incentives for investigation of harms.

Last winter, the likelihood that a child without risk factors would die from swine flu was less than one in a million [15]. When such a high proportion of children develop moderate to severe febrile reactions to the influenza vaccine, it's likely that more harm than good will occur by vaccinating the entire population.

If such a large proportion of children develop high fevers, it is also likely that a substantial number will develop febrile convulsions as a result of vaccination. It is thus surprising the vaccine was approved for this age group. It is also surprising that more explicit warnings about the high risk of adverse reactions were not given to parents when their children were being vaccinated. Passive surveillance (as in Australia and elsewhere) is a relatively weak mechanism to detect and evaluate post-vaccination adverse events [16].

Unlike most drugs, vaccines are used on a population basis triggered by public health policy. As such, evidence of their safety and efficacy needs to be extraordinarily rigorous and evaluation methods and data should be open to independent scrutiny. We need much better and larger studies on both safety and efficacy before we roll out influenza vaccine programs to all populations, especially to children who appear to have much higher rates of adverse reactions. Finally, decisions to use a vaccine in a population must consider its safety profile, but principally its effectiveness. There is poor evidence on how well influenza vaccines prevent any influenza complications in children [10] and other age groups. There is good evidence that influenza vaccines study reports cherry pick results and achieve spurious notoriety [17]. Exposing human beings to uncertain effects is a risky business.

References
1. Sweet M. Australia suspends seasonal flu vaccination of young children. BMJ. 2010 May 4;340(may04_2):c2419. http://www.bmj.com/cgi/content/extract/340/may04_2/c2419

2. Reed J. Flu reactions cause still unclear [Internet]. 6minutes. 2010 Apr 27 [cited 2010 May 5];Available from: http://www.6minutes.com.au/articles/z1/view.asp?id=516097

3. Bita N. Suspended flu jab caused fits in 67 kids [Internet]. The Australian. 2010 Apr 30 [cited 2010 May 5];Available from: http://www.theaustralian.com.au/new...-fits-in-67-kids/story-e6frg8y6-1225860374357

4. Simmons A. Flu jab scare sparks call for surveillance system [Internet]. 2010 23T16:38:00+10:00 4 [cited 2010 Apr 24];Available from: http://www.abc.net.au/news/stories/2010/04/23/2881522.htm

5. U.S. National Vaccine Advisory Committee. Report on 2009 H1N1 Vaccine Safety Risk Assessment [Internet]. 2010 Apr 28 [cited 2010 Apr 30];Available from: http://www.hhs.gov/nvpo/nvac/reports/vsrawg_report_apr2010.html

6. CSL. Fluvax Inactivated Influenza Vaccine (Split Virion). Product information [Internet]. 2009 Nov [cited 2010 May 5];Available from: http://www.csl.com.au/s1/cs/auhq/1217017237558/Web_Product_C/1196562642777/ProductDetail.htm

7. Nolan T, McVernon J, Skeljo M, Richmond P, Wadia U, Lambert S, et al. Immunogenicity of a Monovalent 2009 Influenza A(H1N1) Vaccine in Infants and Children: A Randomized Trial. JAMA. 2010 Jan 6;303(1):37-46. http://jama.ama-assn.org/cgi/content/full/303/1/37

8. Nolan T, McVernon J, Skeljo M, Richmond P, Wadia U, Lambert S, et al. Immunogenicity of a Monovalent 2009 Influenza A(H1N1) Vaccine in Infants and Children: A Randomized Trial. JAMA. 2010 Jan 6;303(1):Supplementary online content. http://jama.ama-assn.org/cgi/content/full/2009.1911/DC1

9. World Health Organization. Safety of pandemic vaccines [Internet]. 2009 Aug 6 [cited 2009 Aug 14];Available from: http://www.who.int/csr/disease/swineflu/notes/h1n1_safety_vaccines_20090805/en/index.html

10. Jefferson T, Rivetti A, Harnden A, Di Pietrantonj C, Demicheli V. Vaccines for preventing influenza in healthy children. Cochrane Database Syst Rev. 2008;(2):CD004879. http://www3.interscience.wiley.com/homepages/106568753/CD004879_standard.pdf

11. Jefferson T, Smith S, Demicheli V, Harnden A, Rivetti A. Safety of influenza vaccines in children. Lancet. 2005 Sep 3;366(9488):803-804.

12. Sebelius K. Pandemic Influenza Vaccines--Amendment [Internet]. 2009 Jun 25;Available from: http://edocket.access.gpo.gov/2009/pdf/E9-14948.pdf

13. Lakhani N. Swine flu in Britain: The guessing game [Internet]. 2009 Jul 19 [cited 2009 Aug 11];Available from: http://www.independent.co.uk/life-s...flu-in-britain-the-guessing-game-1752302.html

 

[Emily]

Re: Australia. Trivalent flu shots suspended after kids hospitalised, fatality

Here's an October 8, 2010 update from Australian authorities regarding the investigation.

http://www.tga.gov.au/alerts/medicines/vaccine-overview.htm

 

[tetano]

Re: Australia. Trivalent flu shots suspended after kids hospitalised, fatality

New theory on why CSL?s flu vaccine caused febrile convulsions in children


A paper published in the Medical Journal of Australia today provides a possible reason for CSL?s 2010 flu vaccine causing febrile convulsions in children. The authors hypothesise that suboptimal use of the detergent called deoxycholate ? used in the manufacturing process by CSL (one of the few vaccine manufacturers that use it) ? to split the flu virus from its membrane may be at fault.

Professor Anne Kelso, Director of the WHO Collaborating Centre for Reference and Research in Influenza, explains the manufacturing process of flu vaccines and provides the context for understanding the authors' hypothesis.

What goes into influenza vaccines and what?s the process of manufacturing? The paper describes CSL?s influenza vaccine as a trivalent vaccine so let?s start with that.

...


http://theconversation.edu.au/new-t...e-caused-febrile-convulsions-in-children-3426

 

[Emily]

http://onlinelibrary.wiley.com/doi/10.1111/irv.12337/full

Li-Kim-Moy et al. (2016) The manufacturing process should remain the focus for severe febrile reactions in children administered an Australian inactivated influenza vaccine during 2010. Influenza and Other Respiratory Viruses 10(1), 9?13. [h=3]Keywords:[/h]

• Adverse events;
• CSL ;
• febrile seizures;
• fever;
• influenza vaccine;
• safety

[h=3]Abstract[/h]
Influenza vaccine safety is an ongoing issue. In 2010, inactivated trivalent influenza vaccines (TIVs), Fluvax[SUP]?[/SUP] and Fluvax Junior[SUP]?[/SUP] manufactured by CSL Biotherapies (?CSL?), Parkville, Australia, were associated with a marked increase in febrile seizures (FS) in children <5 years old. Extensive investigations initially failed to identify a root cause. The company's researchers recently published two papers outlining their latest findings. Cytokine responses to TIV were measured in paediatric whole blood assays (WBA); NF-κB activation was assessed using a HEK293 cell line reporter assay. CSL suggest that the combination of new influenza strains (H1N1 A/California/7/2009 and B/Brisbane/60/2008), increased complexes of viral RNA and lipid in the vaccine, and inherent sensitivities of some children <5 years old caused elevated inflammatory responses resulting in FS. Whilst the papers provide insight into pathogenesis, much remains unclear. The WBA were from only 10 ?healthy? children, potentially affecting generalisability of the results and reliability of these in vitro tests in assessing future influenza vaccine safety. Increased fever rates (without FS) found in CSL TIV studies between 2005 and 2010 suggest a long-standing contribution to reactogenicity from the manufacturing process. More detailed comparisons with non-CSL vaccines would have helped elucidate the relative contribution of patient/strain factors and the manufacturing process. The focus remains on manufacturing process differences as the key causative factor of elevated febrile responses. Studies underway, of modified vaccines in young children, will determine whether reactogenicity issues have been successfully addressed and whether CSL TIV can be relicensed in children <5 years of age.

Full text at link.

 

[Andre DuMouchel]

Thank you for the follow up