global advisory committee on vaccine safety (gacvs) · 4/1/2014 · (hpv) slide ii since...

GACVS December 2013 report 1 |

Global Advisory Committee on

Vaccine Safety

(GACVS)

Report on GACVS meeting

11 – 12 December 2013


Topics Discussed

Safety profile of Japanese encephalitis (JE) chimeric vaccine

Safety of inactivated poliovirus vaccines (IPV)

Increased occurrence of febrile seizures with a seasonal influenza

vaccine

Update on intussusception following rotavirus vaccine administration

Human papillomavirus vaccines safety (HPV)

Vaccine safety monitoring manual

Agenda items on the horizon


Safety profile of Japanese encephalitis (JE)

chimeric vaccine

June 2013 GACVS: no significant concerns regarding the safety profile of – 1 live attenuated

– 2 inactivated JE vaccines based on the SA 14-14-2 strain

December 2013 GACVS: Pre- and post-licensure safety and immunogenicity data of

novel chimeric live JE vaccine (Imojev*) licensed in Australia, Malaysia, the Philippines

and Thailand:

– Pre-licensure data available for 2486 adults and 2248 children (9–18 months at first dose).

– Vaccine is immunogenic

• Does not appear to be affected by concomitant administration of MMR vaccine

– Short-term safety data

• Injection site and systemic reactions reported by >10% of vaccine recipients

• Significantly lower reaction rates in adult population compared to mouse brain-derived vaccine.

– Post-licensure safety experience with Imojev is limited (49,000 doses administered)

• Larger safety database will be necessary to evaluate the risk of rare adverse events.

*includes Yellow Fever 17D and JE SA-14-14-2 vaccines strains


GACVS Advice - Safety profile of Japanese

encephalitis (JE) chimeric vaccine

Additional information would be useful on potential environmental safety issues for

chimeric vaccines, including theoretical risk of reversion or genetic reassortment with:

– wild-type JE viruses

– other circulating flaviviruses (vaccine virus could acquire neurotropic and/or infectivity properties)

– vaccine virus transmission through mosquito hosts (remote biological plausibility)

Post-licensure studies essential in countries where widespread use of JE chimeric vaccine

is planned/in place

Surveillance should include active surveillance of cases of encephalitis and laboratory

determination of the etiology

Safety data on JE vaccines in immunocompromised persons and pregnant/lactating

women is limited


Safety of inactivated poliovirus vaccines

(IPV)

In line with the Polio Eradication & Endgame Strategic Plan, GACVS focused on: – IPV safety record

• Controlled clinical trials in development of available stand-alone and combination vaccines

– Adverse events following immunization (AEFI) reports related to IPV from USA (VAERS)

– Issues related to manufacturing process for IPV

Currently, IPV offered as individual vaccine and combination vaccine for primary

immunization and boosters – Safety data available:

• Stand-alone IPV: known AEFI are limited to non-serious reactions (most common: local reactions)

• IPV as combination vaccine: AEFI are difficult to differentiate from those induced by vaccines in combination (e.g. DTwP)

Reviews have not documented any serious AEFI related to IPV

IPV administered prior to OPV reduces risk of VAPP compared to exclusive OPV series


Safety of inactivated poliovirus vaccines

(IPV) slide II

In the USA, IPV replaced OPV in childhood immunization schedule in 1997 – Currently 1 IPV standalone vaccine & 3 combination vaccines are licensed/available.

VAERS data 1999-2012: in all age groups most AEFI reported were

non-serious – <1% of reports were for IPV given alone

Vaccines most commonly co-administrated with IPV are: – Pneumococcal conjugate

– Haemophilus influenzae type b

– Hepatitis B

– DTaP

– Rotavirus vaccines

Sudden infant death syndrome (SIDS) is most commonly coded for all IPV-containing

vaccines – However, the Institute of Medicine rejected a causal relationship between SIDS and multiple vaccines (IOM

review, 2003)


GACVS advice - Safety of inactivated

poliovirus vaccines (IPV)

Based on available data, GACVS is reassured that IPV and IPV-

containing vaccines have an excellent safety profile.

GACVS was presented an overview of the manufacturing process of IPV

by a licensed vaccine manufacturer – GACVS noted complexities of the manufacturing process

• methods used to ensure virus inactivation and containment to prevent accidental environmental contamination

WHO discussed plans for IPV vaccine technology transfer to emerging

country vaccine manufacturers

– GACVS noted, given the complexities of the IPV manufacturing process, the importance of appropriate

technical support, training & regulatory oversight to IPV vaccine manufacturers


Increased occurrence of febrile seizures

with a seasonal influenza vaccine (Fluvax)

GACVS reviewed updates from the Australian Therapeutic Goods

Administration and the Australian manufacturer CSL on Fluvax (trivalent

influenza vaccine) – Associated in 2010 with increased risk of fever and febrile seizures, particularly in children aged <5 years

– Consequently suspended for 3 months

• Subsequent investigations confirmed that no other TIVs were associated with this increased risk

• Now contraindicated in children <5 years and avoided in those <9 years

– CSL conducted several analyses to clarify etiological mechanism of increased pyrogenicity

• Most of the signal being measured was from complex split viral structures containing lipid and RNA fragments

– Particularly evident with the A/California and B/Brisbane strains used in the 2010 SH TIV

– CSL studies also showed that modifying manufacturing process to increase percentage of splitting agent

resulted in:

• Decreased RNA and lipid content

• Overall reduction in the in–vitro cytokine signature produced by the lipid/RNA fragments

3 Stratton K et al. Immunization safety review: vaccinations and sudden unexpected death in infancy. Institute of Medicine (IOM), 2003randomised controlled phase 3 trials. Vaccine. 2010; 28:7993-8000


GACVS Advice - Increased occurrence of febrile

seizures with a seasonal influenza vaccine

GACVS noted that the virus splitting process used by CSL differs from that used by

other manufacturers

CSL informed GACVS of a modification to the vaccine manufacturing process

planned for 2014 – Will reduce/eliminate possible contributing factors, and reduce additional pyrogenicity

GACVS recommended that PMS data in healthy adult - non-pregnant - subjects be

examined to ascertain the impact of the new manufacturing process – Once shown to be safe, the safety of Fluvax could then be considered in pregnant women

GACVS concurred with TGA’s contraindication of the use of present CSL vaccine in

children <5 years took note of programmatic measures mandated by TGA to reduce

inadvertent vaccination measures (e.g. package labelling)

The events illustrate the importance of post-licensure brand-specific safety

surveillance which presents particular challenges with seasonal influenza vaccines


Update on intussusception following

rotavirus vaccine administration

GACVS 2011 meeting: Review of Rotateq and Rotarix showed a good

safety profile for both vaccines – But may be associated with (up to 6-fold) increased risk of intussusception after the first dose in some

populations

In current meeting, new data from Australia and the USA were reviewed

to update the assessment

Australian data

– Data from a recently published study of intussusception cases from national hospitalization databases,

and active hospital-based surveillance from 2007-2010 suggest a significant risk of intussusception after

the 1st and 2nd dose of both vaccines

– Average vaccine-attributable risk for intussusception (relative incidence in 1–21 days after dose 1 and

1–7 days after dose 2), was estimated to be 5.6 additional cases per 100 000 vaccinated infants


Update on intussusception following

rotavirus vaccine administration (II) USA data

VAERS data: – Rotateq: 584 confirmed reported cases of intussusception for 47 million doses distributed 2006-2012.

Cluster of cases observed between days 3 and 6 after doses 1 and 2

– Rotarix: 66 confirmed intussusception cases reported for 7.4 million doses distributed

Vaccine Safety Datalink (network of linked databases involving 9 integrated health-care

delivery institutions) data: – Rotarix: small cluster of cases, with 6 cases of intussusception for 200 000 doses administered

– Rotateq: no such cluster found. 8 intussusception cases identified (4 each after dose 1 and dose 3) for 1.3 million

doses administered

Post-licensure Rapid Immunization Safety Monitoring system (sentinel-like system using

claims data from national health insurance companies) – Rotateq: data suggest association with clusters of intussusception cases (attributable risk approximately 1 case per

100 000 doses)

– Rotarix: number of cases currently too small to allow calculation of attributable risk


GACVS Advice - Update on intussusception

following rotavirus vaccine administration

GACVS acknowledged that findings from both countries tend to confirm a risk of

intussusception following administration of both vaccines, in particular during first 7

days following a first dose

It noted that attributable risk estimates vary across studies – May be due to differences in background rates of intussusception (estimated to be double in Australia

compared to the USA) or due to uncontrolled biases from sampling uncertainty and limitations of

surveillance systems

Overall, findings remain reassuring that risk of intussusception following current

rotavirus vaccines remains small compared to benefits of preventing impact of

severe diarrhoea

Rotavirus vaccine introduction in other parts of the world should be accompanied

by similar active intussusception surveillance studies together with rotaviral

disease surveillance to ascertain benefits and risks with relevant evidence


Human papillomavirus vaccines safety

(HPV)

GACVS meeting June 2013: – Review evidence from USA, Australia, Japan, GlaxoSmith-Kline (Cervarix) and Merck (Gardasil) related to

autoimmune disease and HPV, with a focus on multiple sclerosis (MS)

– With >175 million doses distributed worldwide and more countries offering the vaccine through national

immunization programmes, the Committee continued to be reassured by the safety profile of the available

products

– Serious adverse events reported as potential signals (e.g. Guillain-Barré syndrome, seizures, stroke, venous

thromboembolism, anaphylaxis and other allergic reactions) were not confirmed in investigations

– Surveillance of pregnancy outcomes among women inadvertently vaccinated during pregnancy through

spontaneous reports and registries has not detected any adverse outcomes above expected rates

GACVS meeting Dec 2013: – Allegations have continued to surface in public about the safety of the vaccine despite epidemiologic studies

showing no increased risk of autoimmune disease (including MS)



(HPV) slide II Since introduction of HPV vaccines, autoimmune diseases have been under

careful investigation given their correspondingly high age-specific background

incidence.

A register-based cohort study in Sweden and Finland (almost 1 million girls aged

10–17 years, 300 000 vaccinated against HPV) did not show evidence of any

association between exposure to HPV vaccine and autoimmune, neurological, and

venous thromboembolic adverse events

USA

– Observational study of 200 000 girls and young women who received at least 1 dose of HPV

vaccine found no significantly increased incidence of 16 investigated autoimmune diseases in the

vaccinated compared to the non-vaccinated group (incl. incidence of MS - incidence rate ratio

1.37, 95% CI 0.74–3.20)

– A pooled analysis of data from 11 clinical trials involving participants >10 years (16 142 receiving

Cervarix, 13 811 receiving placebo/ aluminium hydroxide/1 of 2 different hepatitis A vaccines)

found no increased risk after administration of Cervarix



(HPV) slide III

GACVS provided with an overview of cases that were the

subject of concern in France – One case of MS that had been adjudicated by a French Regional Commission for

Conciliation and Compensation

– Another 14 cases of MS were reported through regional pharmacovigilance centres

and/or the manufacturers to the European Medicines Agency

– All 15 cases had been classified as being of “doubtful” causality according to the

French grading system

– The overview from France included results of a cohort study involving 2 million girls

aged 12–16

• Lack of increase in hospitalization rates for autoimmune diseases among those who received the

HPV vaccine (2.1/10 000 patients/year) compared to those who did not (2.09/10 000 patients/year)


GACVS advice - Human papillomavirus

vaccines safety (HPV) slide IV Multiple studies have demonstrated no increase in risk of

autoimmune diseases, including MS, among girls who have received

HPV vaccine compared to those who have not

GACVS remains reassured by the safety profile of the vaccine, but

noted: – Importance of continued surveillance and epidemiological investigation

– Necessity of collection of high quality data for interpretation of any adverse events which may

occur following vaccination

Allegations of harm due to vaccination based on incomplete

information may lead to unnecessary harm when effective vaccines

are not used


GACVS Statement on the Continued Safety

of HPV Vaccination, 12 March 2014

Summary of GACVS work reviewing HPV vaccine safety (last 6 years)

GACVS has reviewed evidence on: – Syncope, venous thromboembolism, adverse pregnancy outcomes, Guillain Barré syndrome, and stroke, aluminum adjuvants, autoimmune

diseases, and chronic pain syndromes including complex regional pain syndrome

GACVS continues to affirm that HPV vaccine benefit-risk profile remains favorable – Close monitoring of safety

– Careful examination of the available evidence

Committee is concerned by reports of anecdotal observation-based claims of harm – Absence of biological or epidemiological substantiation

– Interpretation of adverse event reports requires due diligence and great care

– Allegations of harm from vaccination based on weak evidence can lead to real harm

– Safe and effective vaccines cease to be used

To date, no scientific evidence that: – Aluminum-containing vaccines cause harm

– Presence of aluminum at the injection site is related to any autoimmune syndrome

– HPV DNA fragments are responsible for inflammation, cerebral vasculitis or other immune-mediated phenomena

http://www.who.int/vaccine_safety/committee/topics/hpv/GACVS_Statement_HPV_12_Mar_2014.pdf



GACVS reviewed a draft document based on a recent publication by the WHO Regional

Office for the Western Pacific *

GACVS advised that a global version should be designed primarily for immunization

programme managers (at all levels) and for regulatory authority staff focusing on: – General principles of immunization, AEFI detection, reporting, investigation, analysis and follow-up activities

– Guidance on the systems and functions required of AEFI surveillance, and the channels of communication of

safety data, as well as including sample forms that can be adapted by individual countries

The manual should not be exhaustive with respect to all vaccine safety monitoring

principles and methods but provide links to the appropriate references and materials

The new manual should limit its content to an explanation of the need for and basic

principles of causality assessment and the purpose, general principles and outcomes of

causality assessment, without advanced technical discussion

* Immunization safety surveillance guidelines for immunization

programme managers on surveillance of adverse events following

immunization (Second Edition). World Health Organization,

Western Pacific Region, 2013.



Links to periodically updated e-documents such as the AEFI rate sheets *will be more

helpful than incorporating them into the main text of the manual which could quickly

become outdated

GACVS advised on some important aspects to be addressed in the manual : – Describe the general structure of an AEFI surveillance system with particular focus on relationships between

immunization programmes and regulatory agencies

– Stress the importance of vaccine safety communication to the community, to decision makers and to all

levels of immunization services

– Focus on general principles of clinical interventions or recommended diagnostic methods for specific AEFI,

given the diversity of current clinical practices and health-care resources

The manual should include generic forms for use in surveillance of vaccine safety and

investigation of serious AEFI – Likewise, it should provide access to the content of the aide-memoires on AEFI investigation and causality

assessment

* See http://www.who.int/vaccine_safety/initiative/tools/vaccinfosheets/en/index.html


June 2014 meeting

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global advisory committee on vaccine safety (gacvs) · 4/1/2014 · (hpv) slide ii since...

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