|
Flu Wiki Forum
Welcome to the conversation Forum of Flu Wiki
This is an international website intended to remain accessible to as many people as possible. The opinions expressed here are those of the individual posters who remain solely responsible for the content of their messages.
The use of good judgement during the discussion of controversial issues would be greatly appreciated.
|
Tue Feb 13, 2007 at 21:24:23 PM EST
|
( - promoted by SusanC)
Is it possible to have a pandemic vaccine for the whole world |
| SusanC :: Enough Pandemic Vaccine for the Whole World? |
within the first six months of a pandemic caused by H5N1?
UPDATE I believe the biggest obstacle to a pandemic vaccine was the mistake made very early on, to tie this to the seasonal vaccine. That mistake in thinking has brought us to the present state of paralysis.
Let's look at the numbers based on current seasonal flu vaccine production techniques and capacity: (I'm keeping all antigen calculations as ug for ease of discussion)
- world population: 6.6 billion
- 86% of the world's population live in countries with no vaccine producing capacity
- 9 countries produce >95% of all doses
- global influenza vaccine distribution: 300 million trivalent (= 15ug x 3 x 300 million = 13.5 billion ug)
- HPAI H5N1 is lethal to chickens, cannot be grown by usual egg-based methods, requires an additional reverse genetics (RG) engineered process
- RG engineered H5N1 has poor yield in egg-culture, only 1/3 of normal antigen harvested from each egg, therefore annual yield is reduced to 13.5/3 = 4.5 billion ug antigen
- inactivated subunit vaccine poorly immunogenic
- non-adjuvanted vaccine needs 90ug x 2 doses (=180ug per person, or 1188 billion ug antigen for 6.6 billion people)
- if we aim at vaccinated just under 50% of world population ie 3 billion, the requirement is 540 billion ug
- with addition of alum as adjuvant, the antigen dose can be reduced to 10ug (whole virus, China), 5ug (whole virus, Japan), or 3.75ug (subunit or whole virus, GSK)
- equivalent to 60/30/22.5 billion ug respectively for world population ie lowest is still at 5x annual capacity
- using MF59 or other oil-based adjuvants, there may be a further but slight reduction
Some regulatory issues:
- current standards are based on providing immune protection for individuals against infection during seasonal flu, not for production of herd immunity to stop pandemic
- in the US, pandemic vaccine license is based on existing seasonal flu vaccine license
- manufacturer also has to have at least 1 FDA approved vaccine, adding at least 2 years for a new company to successfully license a pandemic vaccine
- current requirements incentivize towards producing enough doses and efficacy for seasonal flu; they carry no incentive for innovation towards producing massive doses of a low efficacy vaccine
- there are regulatory barriers to sharing of technology (although BARDA seeks to reduce that)
- FDA has no specific mandate in facilitating technology sharing and resolving intellectual property (IP) issues
- liability protection is being offered
So do we have a chance? Of producing enough vaccines for the world?
There are 2 candidate vaccines worth looking at.
OPTION #1
The first one is the live attenuated vaccine by MedImmune, (the seasonal flu version being FluMist), described in this study in PLOS, Live, Attenuated Influenza A H5N1 Candidate Vaccines Provide Broad Cross-Protection in Mice and Ferrets. The paper is free, and I am only going to quote part of its editorial comment here:
The researchers developed vaccines using three artificially constructed, weakened forms of the H5N1 influenza virus....from H5N1 viruses isolated from human cases during three different years: 2004, 2003, and 1997. They grew larger quantities of the resulting viruses in hen's eggs, and tested the vaccines in chickens, ferrets, and mice.
In tests of safety, the study found that, unlike the natural viruses from which they were derived, the vaccine strains did not cause death when injected into the bloodstream of chickens, and did not even cause infection when given through the birds' breathing passages. Similarly, while the natural viruses were lethal in mice at various doses, the vaccine strains did not cause death even at the highest dose. In ferrets, infection with the vaccine strains was limited to the upper respiratory tract, while the natural viruses spread to the lungs and other organs.
In tests of protection, all mice that had received any of the three vaccines survived following infection with any of the natural viruses (so-called viral challenge), while unvaccinated mice died following viral challenge. This occurred even though standard blood tests could not detect a strong immune responses following a single dose of vaccine. Challenge virus was detected in the lungs of the immunized mice, but at lower levels than in the unvaccinated mice. Mice given two doses of a vaccine showed stronger immunity on blood tests, and almost complete protection from respiratory infection following challenge. In addition, mice and ferrets that had received two doses of vaccine were protected against challenge with H5N1 strains from more recent outbreaks in Asia that differed substantially from the strains that were used for the vaccine.
This study shows that it is possible to create a live, attenuated vaccine based on a single H5N1 virus that can provide protection (in mice and ferrets, at least) against different H5N1 viruses that emerge years later.
Tests of one of the vaccines in human volunteers in carefully conducted clinical trials are currently under way.
Advantages:
- According to the manufacturer, their egg-based production technique for this vaccine is 180x more efficient than for inactivated vaccines.
- only one dose is required
- needle-free delivery - can be self-administered under supervision, so you can vaccinate large numbers in one sitting.
- purification standards are lower than injected vaccines, so it is possible to consider using animal vaccine production facilities
- global avian LAIV production in 2006 50 billion doses
UPDATE An important point was brought to by attention by David Fedson, that even though the global avian vaccine production capacity is huge, apparently LAIV cannot be produced in the same type of eggs as those used for inactivated vaccines. LAIV requires specific pathogen-free (SPF) eggs, the supply of which is not large and is difficult to expand. Still, his estimate is probably several billion doses can be produced in a matter of months.
Hurdles:
- huge regulatory hurdles, national and international
- needs global leadership to facilitate sharing of technology and capacity (MedImmune has technology, others have the capacity)
- distribution, equity, funding, etc
- political will - need co-operation of WHO, FDA, EMEA, and other bodies as well as government and commercial input
OPTION #2
Efficacy of a trivalent recombinant influenza vaccine - Manon Cox
This vaccine is based on the haemagglutinin (HA) protein only, without any other components of the virus. The process is shown in the following slide (click to enlarge)
Protein Sciences is a small company based in Connecticut. The seasonal flu version of this vaccine FluBlok, is at the final stages of being licensed, which should happen some time this year. The H5 vaccine was tested by J Treanor and published in Vaccine 2001 Safety and immunogenicity of a recombinant hemagglutinin vaccine for H5 influenza in humans
Abstract
Recent outbreaks of avian influenza in humans have demonstrated the need for vaccines for influenza viruses with pandemic potential. Recombinant hemagglutinins are an attractive option for such vaccines because they do not require handling potentially highly pathogenic influenza viruses for vaccine production. In order to evaluate the immunogenicity, optimum dosing and timing of administration of a recombinant baculovirus-expressed H5 HA (rH5) in humans, 147 healthy adults were assigned randomly to receive intramuscular rH5 as two doses of 25, 45 or 90 ug each, one dose of 90 ug followed by a dose of 10 ug, or two doses of placebo, at intervals between doses of 21, 28 or 42 days. All doses of rH5 were well tolerated. The rH5 vaccine was modestly immunogenic at high dose. Neutralizing antibody responses to a titer of 1:80 or greater were seen in 23% (14/60) of individuals after a single dose of 90 ug, and in 52% (15/29) after two doses of 90 ug. Varying intervals between doses from 21 to 42 days had no significant effect on antibody responses to vaccination. These results suggest that baculovirus-expressed H5 HA can induce functional antibody in individuals who have not had prior exposure to H5 viruses, but that further studies to improve the immunogenicity of the vaccine are needed.
Advantages:
- This vaccine had already been given to 200 healthcare workers in Hong Kong after their 1997 outbreak, with good antigenic titers
- short production time - 6 weeks from gene to product
- use pure protein instead of H5 virus, no biosecurity risk
- cell-culture based, no need for eggs
- company's own 10,000L bioreactor can make 1million doses of 135ug rHA vaccine in 5 days.
- global capacity is huge. According to Fedson and Dunnill (unpublished observations) a conservative estimate using 25% of global bioreactor capacity can produce an adjuvanted 3.75ug rHA vaccine for 3.4 billion people in 3 months, greatly exceeding any capacity to vaccinate.
Hurdles
- Regulatory - Protein Sciences needs to fulfill FDA requirements of having 1 licensed product first, and having a seasonal flu vaccine using the same technology licensed. Both will be satisfied by licensing FluBlok in 2007.
- This still added a major chunk to time required, and the company's projection is for development of pandemic vaccine in 2009.
- It's a small company, does not have the muscle to lobby or negotiate with regulators, probably needs to be target of acquisition.
As these 2 examples show, the technology already exists to produce enough vaccine for the whole world, even though final trials still need to be done. The technical hurdles are not insurmountable, but the regulatory hurdles are huge. What is needed is political will and leadership, from the WHO, FDA, EMEA and other agencies as well as governments.
Will it happen? Can the world, for once, put aside differences and work towards a global solution to a global problem? I hope so. I'm not optimistic at this point, but I do hope so.
UPDATE There will be no pandemic vaccine (that will alter the outcome of a pandemic) until we switch off the autopilot called 'boosting seasonal vaccine uptake' and switch on our BRAINS! |
|
|
