Re: Man Made H5N1 - Super Version
I thought it might be useful to summarise where we are at this time in relation to pandemic preparedness and interventions for a future H5N1 pandemic, and what issues remain outstanding. The purpose of this review is to highlight how very important continued research into H5N1 is along with research into new and effective countermeasures, and, how important it is that research continues; IMHO the world in not yet ready to deal with an H5N1 pandemic, and anything that can help to 'buy time' and delay or even prevent a pandemic H5N1 emergence should be welcomed. Again, in my opinion, what should be at issue here is not that the research occurs, but what safety measures are put into place to prevent an inadvertant escape and a proper system of evaluation of risks vs benefits of publication of some of the finer details.
What did we learn from the 2009 pandemic?
Vaccines
I would like to look at the issue of vaccines first; without doubt these are still the best defence we have against a hypervirulent influenza pandemic. However, there are significant issues associated with vaccine defences that were confirmed during the pH1N1 experience, despite the best efforts of all concerned...... whether that be WHO or CDC organisations all the way down to the research teams in the labs.
In summary, these learning points were
1. That vaccines cannot yet provide a global answer in the first year or more of a pandemic due to limited vaccine production capacities. Whilst the world has moved towards cell based production systems, these have had issues and are not yet fully on line or capable of addressing global demand in a short time scale.
See on pH1N1 experience
http://www.flutrackers.com/forum/showpost.php?p=353361&postcount=3
2. We are still heavily dependent on egg based vaccine antigen production, which could be a critical issue in the event of an H5N1 pandemic, especially if any human strain is capable of infecting poutry and causing mass die - offs. Sterile egg production is limited at the best of times.
3. From the time of discovery of a pandemic virus it still takes time to reverse engineer the vaccine strain (@3m + - there were significant problems with developing a pH1N1 vaccine strain that would grow in eggs). To counter this the WHO develops H5N1 and other pandemic potential candidate seed vaccine strains; this is in the hope that ones developed ahead of time might be a good match for any emerging pandemic strain and so reduce these vaccine development times. However, if any emerging virus is significantly different to those identified for development as candidate seed vaccine strains, we will be at square one at the time of outbreak.
4. Production of meaningful quantities of vaccine cannot occur for 6 - 9 months after the emergence of a pandemic; by this time the first wave (and possibly a second or more) will have long passed by and done its damage.
5. Once vaccine development issues have been overcome, global annual capacity still has a significant shortfall. There are still the dilemmas presented by vaccine affordability, such that many poorer countries may never gain access to vaccine supplies once they are developed, or may not get sufficient supplies in any meaningful quantities to do much good for their populations. Only countries that can afford to enter into pandemic contracts (or have production capacity on thier territory) can guarantee 'early' (for that read within 12 months) and plentiful vaccine access, although measures have been put in place to reserve a proportion of pandemic vaccines for poorer countries
(see
http://www.flutrackers.com/forum/showthread.php?t=166103).
Adjuvant use can stretch supplies further, but with the recent issues of pandemrix (an adjuvated pandemic vaccine) associated with development of auto-immune disease problems including narcolepsy (I suspect that we will see more auto-immune disease problems that will become visible over time as epidemiology crunches the numbers), such that their use in children and young adults should be questioned ... unless the pandemic is so severe that the benefits outweigh the risks, as was the case for pregnant women with pH1N1
6. If a significant mutation (an immune escape event) or a reassortment event occurs in any emerging pandemic virus, the world has to go back to square one all over again to develop a vaccine that can provide protection.
7. After the pH1N1 pandemic where the world responded as they would for a hypervirulent pandemic, for one that turned out to be 'mild/moderate' I question if there is a) the political will b) the economic will and c) willingness amongst vaccine manufacturers (after broken contracts etc) to make significant further progress to address these outstanding issues.
8. Vaccines, no matter how good a match they may be, are only as effective as their host's immune system capability to transfer vaccination into a long lasting immunity. As studies have repeatedly shown, even vaccines that are an immunogenic 'close match' still only produce immunity in @ 60% of vaccinated individuals aged 18 - 65. Studies have shown even lower levels of protection in older persons as immunosenescence sets in, as well as low protection levels in individuals with compromised immune systems.
In addition to the requirement of an adequate immune response at the time of vaccination to provide influenza immunity, it must also be remembered that even in individuals where vaccination has been effective, vaccination simply primes the immune system to respond to an infection before clinical symptoms set in. It cannot prevent the actual process of infection i.e invasion of virus into the body ... it just primes the bodys response so that the infection is countered rapidly. If this immune response is for any reason impeded, a symptomatic infection can and will still occur. This means that vaccines alone can never be a total global panacea; it is only one half of the equation with the other half being the individuals immune system health and functionality. I would like to look at this issue more in part 2.
My conclusion:[/B] Vaccines are a critical part of the armoury against influenza; however, during the first year or possibly more of a pandemic outbreak they have limited utility due to supply/ production time/ quantity issues.
So what is there that can fill this gap between a pandemic outbreak and vaccine availability/ effectiveness?
At the moment there is only one answer that is 'on the table' and that is oseltamivir or tamiflu. Why only tamiflu?
1. The amantane antivirals rapidly generate resistance in the influenza virus - a single individual will frequently develop a resistant strain over the course of a single infection. Many circulating pandemic candidate viruses already have the genetics that would confer resistance. This rules out 2 out of 4 currently available alternative anti-virals. The issues of resistance are well discussed in the full version of this paper
2. Relenza - the problem with this is it is an inhaled drug, and someone with ARDS or breathing problems is going to find it hard to inhale -a side and apart from producton issues.
3. Peramivir - this is an IV prep so its utility is limited to hospitals.
There is also Ribavirin, which is a highly effective anti-viral that is largely discounted for widespread human use due to its extremely high toxicity and resultant liver damage. This is why no-one seriously considers its widespread use in a pandemic response, even a severe pandemic.
Whilst there are many candidate antivirals in R&D, at the moment, this summarised all of our options for anti-viral drugs; whilst combination therapy could be effective in the short term, it would not be practical (supply/ costs) in a global severe pandemic, and studies indicate that combination use ultimately generates combination resistance.
But its OK isnt it? We still have tamiflu?
Well yes - but as we know from 2007/2008 season when seasonal H1N1 went from 0.1% baseline to 100% resistance in less than 6 months, it is not only likely but probable that widespread and uncontrolled tamiflu usage will produce a resistant substrain.
See
http://www.ncbi.nlm.nih.gov/pubmed/21483816 for a study that examines the changes that were required to produce seasonal H1N1 taimflu resistance, and
http://www.flutrackers.com/forum/showpost.php?p=381359&postcount=1 for further detail on the current evolution of multi-drug resistance.
Worse than this (with regard to H5N1) there is evidence in both Indonesia and elsewhere that resistance markers for tamiflu resistance are emerging in poultry strains that are infecting humans.
See
http://www.flutrackers.com/forum/showthread.php?t=180322.
This raises the spectre of an H5N1 severe pandemic that is either partially or wholly resistant at, or shortly after, emergence. I am not saying that this WILL happen; just that there is a significant risk that it could, and as such, we should plan for this eventuality.
Despite some negative science, Tamiflu's use in human H5N1 cases has shown that it does save lives if used early, even if its justification for use in standard seasonal influenza is perhaps questionable. However, even if tamiflu remains 'the magic bullet' in terms of saving peoples lives in such a pandemic and resistance does not become an issue it has severe limitations:-
1. It must be adminstered early to be effective
2. There are supply/ demand issues
3. It is unaffordable for a very substantial part of the worlds population
So in summary, we are poorly prepared as things now stand. But what could be done? Part 2 to follow.
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