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Thu Aug 06, 2009 at 20:21:50 PM EDT
"The President wants the vaccination effort done safely and quickly." source
Seeing as some of you are signed up to go to the CDC vaccination public engagement meetings, I thought it might be useful to put together in one place, a summary of the situation with regards to vaccine development, current understandings and gaps in science, policy issues, decision-making process etc. The most important thing to remember is planning for this vaccination campaign is a work in progress, with many issues still outstanding, and a lot of changes can happen between now and the moment when the needle hits your arm, including changes as a result of public attitudes and input!!
| SusanC :: Mass Vaccination against Swine Flu H1N1 in the US
|The information is taken from various sources, including but not limited to:
- the CDC, BARDA/ASPR, flu.gov websites
- reports and meeting notes from the National Biodefense Science Board (NBSB) Pandemic Working group meeting and full NBSB teleconference
- notes and slides from the FDA Vaccines and Related Biological Products Advisory Committee (VRBPAC) meetings
- slides and recommendations from the Advisory Committee on Immunization Practices (ACIP) July 29 meeting
I'm going to put everything in bullet-point lists, to make it easier to read. Some are just links, I see no point in copying and pasting information from another page to here, so please visit those links cos they contain valuable information! Also, this is just my good-faith effort based on my understanding at the time of writing. The situation may (and is likely to) change over time. Please refer to the official websites for the most accurate information. And of course, the usual disclaimers about this not being medical advice apply. ;-)
Characterization of novel H1N1 2009
- triple reassortant (ie with genes from swine, avian, and human viruses)
- the HA is antigenically quite close to the HA of the 1976 swine flu virus
- immunity in population
- < 4% of those born after 1980 had detectable antibodies (titer 40 or above)
- 34% of those born before 1953 had antibodies titers 80 or above
- immunity in those recently vaccinated against seasonal flu:
- 2% in children 6 mth - 9 years
- 12-22% in adults aged 18-64
- <5% for those aged 60 or over
- previous vaccination with adjuvanted seasonal vaccine did not confer additional cross protection
Key epidemiological findings
- highest incidence of lab confirmed infections in school age children
- highest hospitalization rates among 0-4 year olds
- hospitalization rates similar to seasonal flu hospitalization rates for school age children and 18-49 year old adults
- fewest cases but highest CFR in older adults
- more case characteristics:
- 50% male
- median age
- all cases: 12 years
- hospitalized cases: 20 years
- deceased cases: 37 years
- underlying conditions
- 70% of hospitalized cases have an underlying medical condition that confers higher risk for complications
- percentage is lower for children and increases with age. See chart below, source.
Licensed seasonal flu vaccines
- 2 kinds licensed in the US - trivalent inactivated subunit vaccine (TIV), made by several companies, and intranasal live attenuated vaccine (LAIV) or FluMist, made by MedImmune
- TIV contains 15ug each of H3N2, H1N1, and influenza B.
- TIV is recommended for age 6 months and over, LAIV is recommended for ages 2 -49
- Children aged 6 months - 8 years who have never received a flu vaccine before, should get 2 doses 4 weeks apart
- However, in the case of LAIV for novel H1N1, only 1 dose is sufficient - the 2-dose recommendation for seasonal LAIV is due to concern of interference between several viral strains, which is not a problem with a single strain
- in general, TIV is more effective in adults, LAIV is more effective in children
- All vaccines are grown in egg culture. There are currently no licensed cell-based influenza vaccine in the US.
- There are currently no licensed vaccines in the US that use novel non-alum adjuvants
- Multi-dose preparations of the TIV contain the preservative thimerosal. Single doses that are thimerosal free are also available. There is no thimerosal in FluMist.
- The CDC website has a number of pages on seasonal flu vaccines - the simplest and most informative page is this summary for clinicians
- Here's a table showing all the Approved influenza vaccines for different age groups including thimerosal content
Immunogenicity vs protection
- immunogenicity testing
- the immune system has 2 ways to generate specific immune responses - antibody-mediated immunity, and cell-mediated immunity
- For an intracellular virus like influenza, cell mediated immunity is more important for protection.
- there are no good or easy ways to measure cell-mediated immunity, so tests of antibody levels are used instead, as 'surrogate markers' to indicate whether a vaccine is expected to be protective.
- based on experience, these 'immunogenicity' tests have some correlation with actual protection, ie ability to protect against infection, but the degree of correlation is imperfect and uncertain
- Protective efficacy
- while the FDA requires a certain proportion of test subjects to achieve a certain antibody level before a vaccine is declared sufficiently immunogenic, such tests can only tell us how protective a vaccine might be, for a population. It's harder to predict the protection level for specific individuals.
- actual effectiveness is measured in a variety of ways, as described here. Effectiveness can vary over a wide range, from 20-90+%, depending on what is being measured, but remember that it's not going to be 100% guaranteed protection!
- How high is enough?
- may not need high antibody level for protection - evidence of priming in 1976 even though no antibodies were detected. (see "Lessons from swine flu 1976")
- in animal studies, ferrets vaccinated with unadjuvanted vaccines were 100% protected against H5N1 even though they had very low or undetectable antibodies, as compared to very high antibody levels for MF59 adjuvanted vaccines reference
Historical development of pandemic flu vaccine
- started in 2005, in preparation for a possible H5N1 pandemic
- the goal was to have the domestic capacity to make 600 million doses of vaccines within 6 months of a pandemic.
- that goal has not been reached yet, more information in this Congressional Budget Office report
- currently, only 1 manufacturer, Sanofi Pasteur, has production facilities in the US
- the H5N1 vaccine was not very immunogenic, and required 6 times the amount as seasonal dose
- the use of novel adjuvants such as MF59 or AS03 was considered, because they are supposed to be 'dose-sparing'
- plans were made to stockpile bulk H5N1 antigen and bulk adjuvant separately, to allow for flexibility in how to use them
- because adjuvants can behave unpredictably with different lots of antigens made by different manufacturers, plans were made to test different adjuvants in combination with vaccines from different companies. These so call 'mix and match' studies on H5N1 were/are being done by the NIH.
- when the H1N1 2009 pandemic broke out, the US government placed orders with various companies.
Supply and availability of novel H1N1 vaccines
- orders placed with several vaccine manufacturers, production has started
- for the inactivated vaccine, the virus yield has been suboptimal, but within planning expectations
- very good yield with the LAIV - vaccine doses likely to exceed manufacturer's ability to make delivery device
- LAIV may be given by dropper - will require EUA from FDA, for unapproved administration of an approved product
- unadjuvanted vaccines can be licensed as a 'strain change' variation to existing license
- use of adjuvanted vaccine will require EUA
- using only licensed unadjuvanted vaccines (Plan A), 150 million doses expected by October, with 80 million per month thereafter
- if using adjuvanted vaccines (Plan B), 312 million doses would be available in October, 160 million doses in November, and 120 million doses in December
- combination (Plan A/B) - allocate unadjuvanted vaccines to special populations eg children, early in the season. Others could get adjuvanted vaccine if they give informed consent. Amount of vaccine available would be similar to Plan B.
- fall epidemic wave will be concentrated (ie 'peaky' due to fast transmission) but asynchronous in different locations
- unlikely to follow seasonal flu pattern, likely to start in September and peak in October
- a third of the population will be sick over 8-12 week period
- severity of illness and groups at higher risk will be similar to currently observed
- absenteeism may reach 30% in some locations
- safety profile and dosage of unadjuvanted vaccines will be similar to that of seasonal flu vaccines
- early data will be available by September/October to confirm dosage and safety for unadjuvanted vaccines
- antigen dose, safety, and immunogenicity of adjuvanted vaccines need more clinical trials - results will not be available till November
- enough licensed unadjuvanted vaccine can be produced for all by Feb 2010
- vaccine delivery will be timely
- distribution and implementation will be challenging.
- liability protection
- may be offered under the Public Readiness and Emergency Preparedness Act
- provides immunity against claims except from 'willful misconduct'
- the Secretary of HHS has to make a PREP Act declaration,
- the declaration has to specify the conditions under which liability protection applies, including disease condition, time period, population affected, geographic limitations, etc.
- more details here
- Emergency use authorization (EUA)
- FDA guidance on EUA available here
- requires a declaration of national emergency by Secy of HHS (on April 25, 2009)
- FDA Commissioner in consultation with Directors of NIH and CDC
- serious or life-threatening condition
- based on scientific evidence, product may be effective
- known and potential benefit outweighs risks
- no adequate, approved, available alternative
- potential alternative product may be considered "unavailable" if there are insufficient supplies to meet fully the emergency need.
- EUA may be for use of unapproved products, eg adjuvanted vaccines
- also for unapproved use of approved products, eg approved vaccine for unapproved age, or variation to the method of administration (eg use of dropper for LAIV)
Lessons from swine flu 1976
- evidence for prior immunity?
- H1N1 virus circulated in humans from 1918 to 1957
- but 1976 swine H1N1 was not descended from the same lineage
- tests done pre-vaccination generally did not show protective antibody levels
- however, most vaccine recipients had very robust immune response after only 1 dose
- conventional wisdom says 2 dose needed for novel subtype
- same experience again in 1977, when another H1N1 escaped from a lab and circulated among people born after 1957
- even young people, born after 1957, had a robust response after 1 dose
- 2009 H1N1 differs from 1976 HA by only 11% (see earlier chart)
- therefore, some experts suggest maybe one dose will be enough for 2009 H1N1
- risk of Guillain-Barre syndrome (GBS) from swine flu vaccine reference
- vaccine first field-tested in 7,000 volunteers
- nationwide campaign - President Ford vaccinated on TV
- initial report of unrelated deaths of 3 elderly people caught public attention
- several hundred people became ill with GBS, 30+ people died
- retrospective analysis - 4.9 to 11.7 cases per 1 million adult vaccinees within 6 weeks after vaccination (background rate should be 0.7-4.6 per million)
- program stopped after 45 million vaccinated
- recent findings on GBS and swine flu
- recent study suggest vaccine HA may be a molecular mimic ie bears enough resemblance to proteins of the nervous system, to cause an autoimmune reaction resulting in GBS.
- other researchers suggest adjuvant effect from high endotoxin (bacterial contamination) content in the vaccine may have played a role
- These 2 studies and their implication were previously discussed here and here
- lessons for mass vaccination
- in a mass vaccination campaign, adverse events purely coincidental to vaccination will occur
- no vaccine is completely safe, so some vaccine-related adverse events are expected
- risks of vaccination has to be balanced against risk of infection
- in 1976, no pandemic occurred - all risks, no benefits
- in 2009, already in a pandemic - people have already died
- risks of vaccination are more acceptable if vaccines available before the peak of the outbreak
- mass vaccination after the peak is worse than no vaccination - all risks, little benefit
- make stepwise, incremental decisions according to evolving situation
- have 'off ramps' in the decision-making process
- too much political buy-in, in public, makes it difficult to change course
ACIP recommendations more details
- priority groups (total 159M)
- pregnant women (4M)
- Household contacts and caregivers for children younger than 6 months of age (5M)
- Healthcare personnel and emergency medical services (14M)
- Children and young adults from 6 months through 24 years of age (102M)
- Persons aged 25 through 64 years who have health conditions associated with higher risk of medical complications from influenza (34M)
- current seasonal vaccine uptake among these groups only 20-50%
- initial demand assumed to be similar to seasonal flu
- recommended strategy - vaccinate as many as possible among targeted group
- further prioritization only if supply limited (total 42M)
- pregnant women (4M)
- Household contacts and caregivers for children younger than 6 months of age (5M)
- Healthcare personnel and emergency medical services (14M)
- Children aged 6m through 4y (18M)
- Children aged 5y through 18 y with chronic medical conditions (6M)
- vaccine also recommended for healthy adults aged 25 - 64 years as availability increases
- vaccine can be offered to those aged 65 or over once demand from the other age groups have been met
IMPORTANT OUTSTANDING ISSUES
One dose per person or two?
- important decision since it affects vaccine availability and the potential need to use adjuvants (see below)
- for LAIV, only 1 dose is enough (see "licensed seasonal vaccine")
- for inactivated vaccine, children under 9 need 2 doses, same as seasonal flu - therefore LAIV preferred
- for most other people, 1 dose may be enough (see above sections 'immunogenicity vs protection' and 'lessons from 1976')
- some sub-populations (eg with health conditions) may need 2 doses
- early clinical trial data may be decisive
- since low antibody level does not preclude protection (see H5N1 and ferrets, under 'immunogenicity vs protection'), one suggestion is to vaccinate clinical trial subjects with inactivated vaccine, then challenge after 3 weeks with the LAIV, ie an attenuated virus, to see if they develop symptoms
- ACIP recommends vaccinating as many people as possible, not to save vaccines for second dose
Use of novel adjuvants
- adjuvants are substances added to vaccines to boost the immune response
- may be 'dose-sparing',
- need lower dose, therefore can vaccinate more people
- ethical issue - dose-sparing brings benefit to others but not to recipient
- may offer more cross-protection to drifted strains
- however, limited evidence of significant superiority over unadjuvanted vaccines (see above reference for H5N1 vaccine in ferrets, under "immunogenicity vs protection")
- adjuvanted vaccines generally cause more vaccine reactions, eg swelling, pain, fever, etc.
- potential for triggering autoimmune disease
- adjuvants act non-specifically, ie they make no distinction between vaccine antigen and self-antigens
- adjuvanted vaccine will provoke a strong immune response, causing swelling and inflammation at injection site
- inflammation causes cell damage, with release of self-antigens that are normally not exposed to the immune system,
- this can activate an immune response against these self-antigens
- the majority of people have immune systems with adequate ability to regulate and suppress such excessive or harmful responses
- for a subset of population with genetic predisposition to autoimmune diseases, a strong inflammatory response triggered by an adjuvant may overwhelm their system, sufficient to trigger an auto-reactive (ie acting against self) immune response
- once triggered, this may progress eventually (but often not immediately) to overt disease, as follows:
- immune responses to external antigens (eg a virus) tend to be self-limiting and stop once the virus is cleared
- autoantigens present a different problem - there is almost infinite supply in the body
- the immune response continues to attack more and more self-antigens in different parts of the body
- such attacks also cause inflammation, resulting in cell damage, releasing even more (different) self-antigens which trigger even more auto-reactive responses
- this creates a self-perpetuating and expanding cycle of inflammation and disease
- The following paragraph is taken from the immunology textbook Janeway's Immunobiology (page 615)
14-11 Chronic autoimmune disease develops through positive feedback from inflammation, inability to clear the self antigen, and a broadening of the autoimmune response.
When normal immune responses are engaged to destroy a pathogen, the typical outcome is the elimination of the foreign invader, after which the immune response ceases, leaving only an expanded cohort of memory lymphocytes. In autoimmunity, however, the self antigen cannot easily be eliminated, because it is in vast excess or is ubiquitous, as with the SLE autoantigen, chromatin. Thus, a very important mechanism for limiting the extent of an immune response cannot apply to autoimmune diseases. Instead autoimmune diseases tend to evolve into a chronic state. There is no cure for such diseases once they are well established - short of a bone marrow transplant that replaces much of the immune system from new cohorts of precursor cells. Even this may not be successful in curing disease.
- in other words, autoimmune diseases once established tend to be chronic and life-long
- there are many autoimmune diseases; together they affect 5% of the population
- genes play a big role, but not everyone who has the genes will develop disease in their lifetime
- the following chart shows twin concordance rates (ie the odds of a second twin getting a disease if the first twin has it) for several diseases.
- for every person who already has an autoimmune disease, there are several more who have the genes but who may not develop disease unless they encounter the right triggers.
- vaccine adjuvants may act as such triggers for an unknown but potentially sizeable portion of the population.
- there are no tests to predict who may be at risk
Clinical trials and safety monitoring
- safety profile of unadjuvanted vaccines expected to be similar to seasonal vaccines
- adjuvanted vaccines need more safety data
- chronic and delayed adverse events due to novel adjuvants are difficult to detect in clinical trials,
- only limited clinical trials of small groups (100 each) possible from manufacturers
- in theory animal models would be very useful, but this area of science is poorly developed - according to Jesse Goodman, Chief Medical Officer at the FDA:
The toxicology of vaccines, not to mention the toxicology of adjuvants has been a really neglected area. And, you know, we've tended to only recently pay attention to this. And we've had just tools of conventional toxicology, which largely focus on drug effects on organs. And, of course, when you are talking about immunotoxicology, there are not a lot of good models. I think there is a huge opportunity for the scientific community to develop better nonclinical or non-human models and even human studies that could tell us about the safety of novel vaccines and adjuvants.
- NIH comment - 'significant preclinical data' still needed to do 'mix and match' studies
- post-marketing 'safety signal' with MF59? reference
- licensed for use in > 65 in Europe,
- usage in non-elderly subjects unknown but expected to be rare
- but 34% of reported adverse events are from non-elderly adults
- the risk of adverse events may be much higher in non-elderly than elderly populations
- attitude and credibility of industry is cause for concern
- GSK representative at FDA meeting stated the effect of adjuvants only limited to muscles and local lymph nodes, and that "there is no biological possibility" for triggering autoimmune disease.
- however, a vaccine given in the muscle is designed to trigger protective response to an influenza virus that will invade via the lungs, ie the effect of vaccines (and adjuvants) are, by design, not limited to injection site
- the 'biological possibility' of adjuvant-induced autoimmune disease is amply demonstrated in decades of use of such adjuvants to induce autoimmune diseases in animal models
- alternatively, see this extensive list of > 4,000 peer-reviewed journal articles on the subject.
In summary, both actual (demonstrable) and perceived safety of vaccines will determine the public's acceptance and the eventual success or failure of this mass vaccination effort.