Vaccine preclinical studies 2

Now we're going to move from the vaccine's safety aspects or toxicology, to the pharmacology aspects, or proof-of-concept. This is the flip side of safety. So safety is the way we try to identify risks and assess risks, and the proof-of-concept studies or mode-of-action studies, are how we try to assess the potential for benefit. So for drugs, pharmacology encompasses the concepts of pharmacokinetics and pharmacodynamics. But in fact for vaccines, those concepts don't really readily apply and what we're really trying to address is the immunological mechanism for protection. So we look at immunogenicity in animals and if there's a relevant animal model, then we try to do studies of challenge-protection. And I'll explain those in more detail in a moment. Often these types of studies are research studies. And in fact, they're rarely, if ever, performed in compliance with good laboratory practices. So even though they're intended to support regulatory decision making about potential for benefit, in fact, the fact that they're not required to meet these good laboratory practice regulations reflects the fact that, in fact, in the US, Phase 1 studies can only be placed on clinical hold for safety. And so really the regulatory decision making, the precision around that has to be on the basis of risk assessment or safety aspects.

Vaccine immunogenicity is key to understanding whether or not a vaccine has any potential to work in humans, and often we'll use an animal model. It's important that these involve a relevant animal model although sometimes it's not easy to identify. And, in fact, often what people will do is move from small animals like mice or guinea pigs to slightly larger animals like rabbits and then to non-human primates. However, if the vaccine is one that replicates as a live vaccine, then you need an animal model in which it will also replicate and replicate in the same tissues that it would in a human. If the vaccine incorporates some species-specific molecule, for example, DNA vaccines or some vectored vaccines will include a cytokine. For example, cytokine encoded in a plasmid to include as an adjuvant for the vaccine. And you may need to use an analogue in a species of choice. For example, if you're looking at a Rhesus cytokine in a Rhesus Macaque to mimic human cytokine in humans. However, often there is more than one animal model used as I explained, and usually people start small and then work their way up. And I'll talk to you in a moment about the limitations of that approach. But the purposes of these vaccine immunogenicity studies really are all around exploring what doses might be needed in order to get an immune response in human. Here, especially if you're using a small animal, you will scale the dose. So, for example, you might use a concentration that is the amount available in 50 micro liters in mice, whereas you would give half a mil or a mil in humans. You might want to explore various aspects of your regimen, so for example, maybe you need to prime-boost approach. Maybe you need more than one inoculation in order to optimize a response. You may need to explore the timing between the inoculations, often a rest period is required to really get an anamnestic response to your immune response. And also you want to be able to look at whether or not you can achieve durability, although sometimes for some vaccines a rapid onset of protection may be more important than a durable protection. You'll also explore in the animal models routes of administration. These might intramuscular, subcutaneous, a dermal route, intranasal, oral, or some other kind of mucosal route. Some people use, for example, suppositories to try to deliver to mucosal surfaces. This is also a good juncture in which to explore whether or not you need to add an adjuvant. And there will be a separate lecture in this series on vaccine adjuvants, but the purpose of adjuvants really are to determine whether or not you can spare dose of the vaccine, whether you can modulate the immune response to change its character to be one that's more protective or to potentiate the immune response to drive it higher than you would be able to do without an adjuvant. And, of course, you want to explore the types of immune responses and the level of immune responses that you can get in the animal model with the vaccine.