Nanotechnology And Vaccines

REGA 505 Date 11/22/2012

Pranchi Sharma- 822221016 Rajeswari Devanathan - 822257226

Nanotechnology and Vaccines

Vaccination is one of the most important parts of modern medicine. Many infectious diseases which used to be almost guaranteed to be fatal are now easily prevented, and many have been eradicated altogether. Nanotechnology is likely to have widespread implications in medicine, and vaccines are no exception. This article explores some of the technologies being investigated by nanotechnology researchers, which could have a profound impact on vaccinations and the wider medical world.

First patent of nanopatch was issued in January 2012. There are around 11 applications pending; in the US, Canada, Europe and other first tier economies, and select emerging markets, or > 90% of the worldwide market for pharmaceuticals. The company continues to file new applications, approximately quarterly.

Types of Vaccination:

1. Passive immunization: Antitoxins and immunoglobulins which provide immediate source of antibody. Ex: Diphtheria anti-toxin, Botulinum anti-toxin, Hep B IG, Tetanus IG

2. Active Immunization: Live vaccines are attenuated (weakened) organism which replicates in the host. Ex: MMR, varicella Killed/inactivated/subunit vaccines are killed micro-organisms, inactivated toxins or other subunits. Ex: Inactivated polio vaccine, DTaP vaccine
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Nanovaccines

One of the most promising areas of medicine where nanotechnology could have a big impact is in drug delivery, which is a very important part of vaccinations, and systems to get antigens into the body without needing an injection could drastically increase the availability of vaccinations, particularly in developing countries where access to trained medical personnel is limited. Delivery systems can also protect the antigen until it reaches the most effective place in the body, allowing the dose to be lowered, which will reduce the side effects for the patient, and, importantly, reduce the cost. Some novel methods of administering vaccines which nanotechnology is making viable include:

1. Oral delivery

Antigens are often fragile, and can be damaged by digestive juices when taken orally. By encapsulating the dose in polymer nanoparticles, the active vaccine material could be preserves until it reaches the bloodstream. The overall dose may have to be higher than normal, however, as some of the vaccine will not be absorbed by the body. It is important, therefore, to make sure that side effects are under control, and the fate of the nanoparticles and the drug is understood.

2. Nasal delivery

Nanoemulsions of vaccines can be safely inhaled in a nasal spray. This is a convenient method of delivery, which does not suffer from the dosing problems of oral delivery. Nanoemulsions are also stable at room temperature for relatively long periods of time, which would allow them to be distributed to remote locations and developing countries more easily. They have been shown to

be effective in administering hepatitis B vaccinations in animal trials, although more study is needed to determine the effects on patients with allergies or respiratory problems.

3. Intra-dermal injection:

This is the conventional method of administering vaccines. Although the less invasive oral and nasal delivery routes would be preferred most of the time, there will be some cases where an injection is necessary, and nanotechnology can still help to improve this technique. Vaccines are injected in combination with an inert material called an adjuvant, which causes the vaccine to pool under the skin and controls its release into the bloodstream. Using biodegradable nanoparticles as the adjuvant could allow the release rate to be tailored more precisely to the immune system of the patient - initial trials show that this improves the immune system's response to the vaccine.

4. Nanobeads:

These are a possible way around the need for separate adjuvants when administering vaccines. By attaching the antigen directly to solid, inert beads, around 40nm in diameter, the immune response is greatly improved - these nanobead vaccines can also be used to treat infection as well as prevent it. As with all novel medicines, significant proof of efficacy and safety is required before even small trials with human patients can begin. The main concerns with nanovaccine technologies are:

variations in toxicity/biocompatibility with nanoparticle size and shape reproducibility of nanoformulations on a large scale toxicity issues, particularly long-term accumulation in organs
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The toxicity of nanoparticles is hard to assess, particularly when trying to rapidly screen a number of nanoformulations for vaccines or other drugs. Many of the adverse effects of nanoparticles on humans are likely to result from long-term, low-level exposure, which is difficult to measure, and requires very long trials to determine.

Researchers are trying to develop higher throughput tests for chemical signatures which appear in the short term which could be indicators of longer term problems. These are difficult to get accurate, however, and our understanding of the long term effect of nanoparticle exposure is still limited.

5. Polymeric Nanoparticles:

PLG have been extensively used to encapsulate antigens. PLG forms lactic and glycolic acids, After hydrolysis of hydroxyl acids, yielding small spherical polymeric particles 1100 nm in size. Adsorbed antigen offer improved stability and activity over encapsulated antigen by avoiding exposure to organic solvents used during formulation and acidic pH conditions caused by degradation of the polymer. These are Biodegradable, biocompatible polymers have been approved for use in humans. Ex: Poly (D,L-lactide-co-glycolide) (PLG) and polylactide (PLA).

6. Viral vectored vaccines:

Viruses size vary in diameter from 20 nanometers (nm; 0.0000008inch) to 250400nm. The immune system quickly respond to viruses, this would seem to be an ideal way to deliver an antigen. It consist of a non-replicating virus that contains some defined genetic material from the pathogen to which immunity is desired. Such vaccines are also commonly referred to as live recombinant vaccines.
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7. Dermal Applications: NanopatchTM array

Penetrates through the protective outer skin layer (stratum corneum) and targets immuneactivating material to the immune-cell rich layers just beneath the outermost skin layer utilising the microprojections with optimised spacing and length. A square patch is kept on the skin for
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two minutes to direct the vaccine. This technique uses 100th part of the dose of a needle and shows equivalent or better performance. Preclinical studies in mouse model are being carried out. 100-fold reduction has been achieved in the mouse model when delivering Fluvax and for amplifying the vaccine efficacy. Pre-clinical experiments have also shown the ability of the Nanopatch to remove or significantly reduce the amount of adjuvant required for effective vaccination. Protrusions can be specifically engineered to ensure delivery directly to immune cells therefore less material is required. It has painless application and no scar tissue formation. Versatility in applications: vaccines, drugs, hormones, wound healing proteins.

There are many advantages involved with nanopath: o Delivery of molecules that normally cannot penetrate the skin o Lower dosages = less side effects o Easy to use, no needle-stick injury, low risk of infection, pain-free o Can be self-administered, or given by a non-medical person o Smaller, lighter, lower transport cost o Mass production = cost benefits o Suitable for public health programs e.g. air-drop into disaster zones o Suitable for veterinary purposes o Biocompatible and biodegradable material used to make patches o Can achieve short- & long-term delivery.

8. Navacim: It is manufactured by Parvus Therapeutics Inc. Calgary. Navacim is a new class of therapeutic; a peptide-MHC complex covalently linked to a nanoparticle.

A. Nanoparticle core gold/iron, B. Surface coating agent Protein component, C. MHC protein, D. Short Anitgenic peptide for specific disease. 10-20 amino acids long Finishes particle size 60nm

Future prospects: Carbon nanotubes may be used to deliver vaccine. Peptidenano-bead based vaccine approach may be beneficial, especially for highly variable pathogens such as FMDV(foot and mouth disease virus). Nano emulsion may deliver smallpox, influenza, anthrax and HIV vaccines. Nanoemulsion anthrax vaccine is the licensed anthrax (Bacillus anthracis) vaccine requires six injections given over six months, and can result in serious adverse events. The experimental anthrax vaccine consists of a recombinant protein from the Bacillus anthracis cell wall adjuvanted with a nanoemulsion of water, soybean oil, alcohol, and a
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surfactant, emulsified into droplets 200 to 300 nm in diameter. This vaccine has been tested in mice and guinea pigs only, and was highly effective in the animal tests Nanoemulsion against GP120, one of the major binding proteins, may induce mucosal and cellular immunity, and neutralize antibody to various isolates of HIV. Adenovirus may deliver vaccine for Alzheimer's disease, influenza, tetanus and HIV based vaccine.

Potential Issues with Nanovaccines:

As with all novel medicines, significant proof of efficacy and safety is required before even small trials with human patients can begin. The main concerns with nanovaccine technologies are:

variations in toxicity/biocompatibility with nanoparticle size and shape reproducibility of nanoformulations on a large scale toxicity issues, particularly long-term accumulation in organs

The toxicity of nanoparticles is hard to assess, particularly when trying to rapidly screen a number of nanoformulations for vaccines or other drugs. Many of the adverse effects of nanoparticles on humans are likely to result from long-term, low-level exposure, which is difficult to measure, and requires very long trials to determine. Researchers are trying to develop higher throughput tests for chemical signatures which appear in the short term which could be indicators of longer term problems. These are difficult to get accurate, however, and our understanding of the long term effect of nanoparticle exposure is still limited.
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Conclusions:

In the next few decades, nanotechnology will have a big impact on all aspects of medicine. The application of nanotechnology to vaccines will make them more effective and less invasive, and may provide opportunities to develop new vaccines for unpreventable or uncurable diseases. Perhaps most importantly, nanotechnology will allow formulations of vaccines which are stable enough to be distributed without refrigeration to villages in the developing world, where access to medical facilities is very limited. This could save many lives, and slow the spread of HIV, malaria, and other major infectious diseases.

References: 1. Tarala Dnandedkar, Nanovaccines: recent developments in vaccination, J.Biosci.34000 0002009. 2. J.Peek Lauraet.al, Nanotechnology in vaccine delivery, Advanced Drug Delivery Reviews60(2008)915928, 3. J.Bharali Dhrubaet.al, Novel nanoparticles for the delivery of recombinant hepatitis B vaccine, Nanomedicine: Nanotechnology, Biology, and Medicine4(2008)311317. 4. Cui Zhengrong et.al, The effect of co-administration of adjuvants with a nanoparticlebased genetic vaccine delivery system on the resulting immune responses, European Journal of Pharmaceutics and Biopharmaceutics 55 (2003). 5. http://www.azonano.com/article.aspx?ArticleID=3070#oral_delivery 6. http://www.good.is/posts/nanotech-jackets-to-keep-vaccines-from-spoiling-off-grid 7. T. Akagi and M. Akashi (*) Department of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan 8. Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology (CREST), Kawaguchi Center Building, 4-1-8 Honcho, Kawaguchi 332-0012, Japan

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