Flu Vaccine: Is the Cure
Worse than the Disease?

Flu Vaccine: Is the Cure Worse than the Disease?

by Tom Reynolds

Have you had your flu shot lately? If so, you probably had a good experience as did the vast majority of your fellow flu shot recipients. For five bucks you got immunity to the flu this year. The only likely side effect was a sore arm - and even that can be avoided thanks to the newly available FluMist nasal flu vaccine.

But an unlucky few suffered side effects. Between 5 to 10 percent of all people immunized experience "adverse events" -- to use the terminology of the vaccine development world -- including mild to moderate flu-like symptoms.

If the cure causes the misery you were trying to avoid in the first place, some folks wonder, "What's the point getting vaccinated?" Well, according to the Centers for Disease Control, getting the shot drastically reduces the chance of getting serious complications from the flu. The vaccination is highly recommended for anyone over 65 or for anyone caring for an immuno-compromised person.

That sounds like sage advice but people still complain. It is only human nature to associate a cause and effect: Most people get the flu vaccine in the fall and winter when other viruses are circulating. If they get a fever or cold from infection with a different virus, they can't tell the difference, and understandably associate it with the vaccine.

Misconceptions about vaccinations are so prevalent that they have taken on an Urban Legend status in our society. For all the good vaccines have done over these years, wiping out hideous diseases such as small pox and polio, some people still regard vaccines with suspicion. This has not gone unnoticed to the researchers and biotech companies that develop vaccines, or the medical professionals who see immunization as the most effective means to prevent outbreaks of emerging infectious diseases.

Immunization compliance issues and the public's fear of vaccination have become significant issues for Public Health Policy makers. For example, fearing sickness and debilitation, significant numbers of American troops in 2000 refused to take mandatory anthrax vaccinations. The vaccine mutiny amounted to more than a PR problem that contributed to the product's temporary recall - it was a setback to the United States' strategic military doctrine to deter biowarfare attacks by embracing immunological protection for soldiers as an alternative to threatening mass retaliation.

Behind the paranoia is the very understandable fear that a vaccine, even one approved by the FDA and prescribed by your doctor, can cause sickness and in rare cases even death. Even the smallpox vaccine, one of the greatest live savers in human history, has a mortality rate of one or two people for every 1 million who take it.

There is a real need to understand what alarms people and develop the means to prevent the vaccines from unduly harming the patient. One approach starts with examining the virus the vaccine is directed against. A hallmark of RNA virus replication is the organism's tendency to introduce point mutations into their genomes. This property reflects the relatively weak fidelity by which viral RNA polymerases make genomic copies for packaging and assembly of daughter virions. From an evolutionary standpoint, the trait confers distinct advantages: Through normal cycles of replication, the virus can introduce changes that enhance natural selection. It may delete or change an epitope that has been targeted for immune attack, for example.

This variability has vexed those who design different versions of viral vaccines, which rely on the stability of point mutations critical for attenuation. The risk of reversion to the more virulent wild form of the virus is the main concern of any new attenuated vaccine entering a clinical trial, and reversion events are strictly monitored after administration of the new vaccine for adverse effects or reduction of the immune response. Any method which could prevent this phenomenon would have significant positive benefits on future vaccine development from both a safety and efficacy standpoint. Currently, there are few, if any direct methodologies available that can prevent such events from happening.

Commonwealth Biotechnologies is pursuing an entirely different approach to the problem. RNAi is a recently developed technique that utilizes an innate immune pathway that destroys double-stranded RNA within cells. Essentially, short hairpin RNAs are introduced into cells that are complementary to the gene that one wishes to turn off or attenuate. Once duplexing of the RNAi/gene transcript takes place, it is rapidly cleaved into non-functional subunits by the cellular RISC complex, in concert with the protein Dicer. This technique is highly specific. A single non-homologous base substitution can render RNAi ineffective, so that one can ablate translation of one transcript while not interfering with the desired translation of a closely related but distinct homologous transcript.

It has been noticed that RNA interference can inhibit virus replication, and number of published studies have demonstrated broad applicability of the technology for this purpose (1-4). These studies have initiated an exciting field of research exploring the potential of RNAi technology for use as a novel antiviral therapeutic approach and as an alternative to traditional vaccine strategies. This research relies on effective introduction of virus-specific RNAi constructs which constitutively express transcripts in target cells.

Thus, another attractive use of RNAi would be to raise the safety profile of live attenuated virus vaccine candidates by co-expression of an RNAi transcript specific for an undesired reversion mutation. These could be directed either to the viral transcripts to ablate translation of viral proteins with virulent properties or to the viral genomes themselves, to prevent synthesis and packaging of revertant strains.

CBI has developed expertise in RNAi technology. Last year, we began supplying our customers with high-quality viral vectors for this purpose. CBI also would like to develop RNAi technology for vaccine use. We recently filed a patent that covers the process for applying the technology to create a vaccine candidate incorporating RNAi expression in order to suppress the occurrence of reversion events using a model vaccine system. CBI is currently exploring the incorporation of this technology into the model vaccine as a safeguard rather than a replacement of the vaccine.

Future studies will reveal the general application and usefulness of this approach. This is not to say there is no need to develop the antiviral therapies, which can be of value. In fact, CBI' studies will provide some basic data, which will prove proof of principal for a development program for therapeutic RNAi approaches in both cell culture and mice studies. However, CBI sees the use of RNAi technology as a therapy for antiviral treatment of infections or use as a vaccine as being very early in its development.

References:

1. Inhibition of Marburg virus protein expression and viral release by RNA interference - Reference

2. Inhibition of influenza virus matrix (M1) protein expression and virus replication by U6 promoter-driven and lentivirus-mediated delivery of siRNA. - Reference

3. Interfering vaccine: a novel antiviral that converts a potentially virulent infection into one that is subclinical and immunizing
Vaccine, Volume 22, Issues 23-24, 13 August 2004, Pages 3018-3025

4. RNA silencing in viral infections: insights from poliovirus
Virus Research, Volume 102, Issue 1, 1 June 2004, Pages 11-1

Commonwealth Biotechnologies, Inc. 601 Biotech Drive, Richmond, VA 23235 800-735-9224 (800-RELY-CBI) FAX: 804-648-2641 email: [email protected]