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Most people think that vaccines provide them with an impenetrable shield against bacterial and viral infections. It’s probably time to rethink that paradigm, shifting the focus from “prophylactic” vaccines that produce antibody to protect against infection – to “therapeutic prophylactic” vaccines that engage the cellular immune system, which could serve to prevent illness, even though infection does take place. Shifting the paradigm is particularly important when it comes to developing vaccines in response to bioterror threats because, the case of an attack, a vaccine would need to be developed and produced in an extremely limited period of time. That task is difficult if not impossible, using traditional means for making vaccines and limiting the type of vaccine that is produced to traditional “prophylactic vaccines”.

The new paradigm would not deviate from the way vaccines actually are known to work – vaccines serve to “prime” the system so that it is ready and able to act in case of challenge – but rather take advantage of an aspect of immune defense that vaccines already engage, to a greater degree than has been done before.  Indeed, the number of vaccines that completely prevent arrest a pathogen before it enters the target cell is surprisingly small. Most vaccines work by means of preventing infection of the target cell and also promoting cellular defense to clear out the pathogen from cells that have been penetrated. In addition, attempts to develop prophylactic vaccines for some diseases such as tuberculosis, hepatitis C, malaria and a number of other serious infectious disease problems have failed, and it may be worthwhile to consider a new strategy for these important globally relevant diseases therapeutic prophylactic vaccines that reduce morbidity and curb mortality while not entirely preventing disease.

What’s the difference between “prophylactic” (traditional) vaccines and the new concept – “therapeutic prophylactic”: vaccines that build cellular immune system body armor? If the immune system is immediately effective against infection, we can consider a vaccine to be ‘preventive’. The bacteria or virus penetrates the body but is cleared immediately by antibodies that bind to the pathogen and clear the infection. If the first line of defense is penetrated, but other systems can come into play, before disease occurs, reducing the severity of the illness, then we can consider the vaccine to be a therapeutic prophylactic (prevents disease but not infection). An example of a therapeutic prophylactic vaccine that is already implemented to prevent human disease is rabies vaccine, which is often given after infection occurs, so as to reduce the chance of severe illness. A number of other vaccines probably also act through this mechanism (such as BCG vaccine, in the developing world context). A third category of vaccines is becoming more familiar due to the recent launch of the “Dendreon” cancer vaccine platform – Therapeutic vaccines. Typically, a therapeutic vaccine is given after the disease is already present, in the hope that the vaccine will reduce the burden of disease or even help the body cure the infection.

Such vaccines could be considered more akin to body armor (the protective gear that soldiers wear in combat) than an impenetrable shield against infection. Take flu vaccine for example. Influenza actually enters the body, where it encounters a first, second, and even third line of defense, which it must overcome to cause disease. Since there are multiple layers of defense, in most cases, all three systems are engaged when influenza (flu) infection occurs. The first line of defense is the “innate” immune system (in the case of flu, this might involve the layers of mucus in the nose and lungs that clear viruses before they can attach to their target cells), The second line of defense against flu is humoral (antibody) response and the third is cellular immunity. Since there are multiple layers of defense, in most cases, all three systems are engaged when infection occurs. Occasionally, the first line or second line of defense is penetrated, and the fallback system is the sole means of defending against infection and disease. Some would argue that this third line of defense was actually engaged during the recent novel H1N1 epidemic – and that T cell immunity reduced the potential for disease. The debate about H1N1 continues, and some vaccine experts believe that the cellular line of defense was in fact responsible for the dramatic difference between the number of people infected with novel H1N1 and the number of cases seen in hospital emergency rooms. So while people were not protected by antibodies (because no cross-reactive antibodies could be identified), they were protected by cellular immune responses against bits of the virus that they had seen before, in the context of seasonal flu vaccination or due to exposure to a previous H1N1 virus.

Therapeutic prophylactic vaccines may also be an important strategy for developing vaccines against unknown-as yet to be identified pathogens. The need for a new approach, especially when the safety of the nation and the lives of civilians are in jeopardy, is self-evident. A number of Department of Defense sources have described attempts by the former Soviet Union to design pathogens that have never been encountered before and for which vaccines could therefore not be developed. For example Vector, the Soviet bioterror design center, actually produced a chimeric Smallpox and Anthrax pathogen, before the program was shut down. Thanks to the advent of molecular biology and genetic recombination techniques, future biothreats could come in the form of a virus, bacteria or other pathogen, which may also encode drug-resistance genes, the varieties of which are only limited by the imagination of the designers.  Identifying and sequencing the pathogens can now be done in very rapid fashion, but how might we better design vaccines to counter that threat? Again, if we can develop vaccines that keep people from getting extremely sick, we buy time to get them from wherever the exposure occurred to a place where they can get treatment.  This is especially useful under the circumstances of an unknown pathogen attack – as you might see with a bioterror event.  A ‘preventive therapeutic’ vaccine that creates just enough immune response to hold disease at bay would keep them alive until they can get to a “medic” and their chances of survival increase enormously.

How can we develop such vaccines? The best vaccines probably prime at least two of the three systems (the innate system is engaged by vaccination and infection but does not have “memory” and so must be engaged each time infection or vaccination occurs) of defense when we develop vaccines and don’t take the rest of the system into consideration.

Why the new approach to vaccines so important for biodefense? Unfortunately, not much is new in the area of vaccine development for biodefense. Most of the vaccines being developed, for example, Anthrax, use the old “shake and bake” approach: Grow up the pathogen, inactivate it in some way, and inject the product in the hopes of creating an immune response. Alternatively, some companies are trying to knock out the “virulence genes” to make live attenuated vaccines – a process that recently failed (despite significant investment by Dynport and the Department of Defense) and is unlikely to yield safe vaccines in the extremely short period of time that would be available for a national vaccine program to be put in place after a bioterror attack. Even flu vaccine production has significant problems, as was demonstrated in the last epidemic. The egg based approach can result in unsafe vaccines (due to bacterial contamination of the eggs) and as was illustrated for novel H1N1, creating a ‘vaccine standard’ for distribution to production centers can be delayed due to virus yield issues

What’s different about FastVax, in terms of, production and deployment? We have created a consortium of companies that have the required expertise that we are calling “FastVax”. The consortium will be led by a team of scientists having expertise in the critical areas of vaccine design, production and delivery. Instantaneous genome sequencing is, as far as we can tell, already well underway, as reflected by the immediate availability of the SARS and novel H1N1 genomes when those epidemics emerged. The FastVax team would pick up where the genome sequences leave off,  turning the genome sequence information into a vaccine is as short a time as possible.

One key element in the FastVax program are computer-driven “immunoinformatics” tools – the iVAX system- that has been developed by EpiVax over the course of the last decade. These tools make it possible to scan multiple, huge genomes in an extremely rapid fashion (fractions of a second) and identify the elements of those genomes can turn on an immune response. Another key element e of the important points about the process is that traditional means of developing vaccines are NOT employed – in other words, we do not have to count on eggs in any step of the process.

How feasible is the approach? The FastVax team is made up of companies having expertise in the three main areas of vaccine development: design, production and delivery. The development is done in a consortium instead of a single company.  Each consortium member is able to make quicker decisions and trouble shoot much more efficiently than a larger more traditional company. The approach is feasible, as each company currently has mature technologies that have been proven to be useful for the development of vaccines. Together companies have the ability to decrease the amount of time needed to develop a vaccine to less than 90 days.

How is this approach different than the traditional approach to making vaccines and why is the approach so rapid? Another key element of the approach the use of DNA vaccine – which enable the “fast vaccines” to be safer, easier to design etc. DNA vaccines have been around for years now and there are no safety concerns; several have been tested all the way up to Phase III trials in humans although none have been implemented for human use. Several vaccines are already commonly used in veterinary practice. .

Why is there such an urgent need for the capability to rapidly develop vaccines? As outlined in the WMD Commission report card defense experts consider the threat of a bioterror attack to be extremely real.  The commission believes there will be an attack sometime in the next 2-3 years. The ability to react swiftly to an attack not only makes us safer but also is a deterrent for terrorists. If we can respond we are less attractive as a target. What needs to be done now is to “test the system”. Once we can implement the program, the sheer ability to make vaccines ‘On Demand” would mean that the Nation has in place a “First line of defense”.