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Cell death suppression increases efficacy of M2 vaccines
January 16, 2008Significant public attention has recently been focused on the development of new anti-influenza (flu) vaccines that provide protection against a broad spectrum of viral strains. One proposed strategy is to utilize conserved viral protein, M2. Clinical trials of M2-containing influenza vaccines were recently initiated by US and European companies.
Scientists from Cure Lab, Inc. in collaboration with Boston University School of Medicine published new findings indicating that unmodified M2 may have a negative effect on anti-influenza vaccination. The researchers also demonstrated how this detrimental effect of M2 can be eliminated, thereby allowing any future M2-containing vaccine to be both broadly protective as well as safe. This study appears in the January 16th issue of the online journal PLoS ONE, which provides free access of its publications to scientists and the general public.
Annual vaccinations against seasonal flu are known to be insufficient to fully prevent disease. The cause of this is a single predicament: current vaccines predominantly target two viral surface proteins, hemaglutinin and neuraminidase that are constantly mutating. Thus, a particular vaccine can be protective against a viral strain carrying matching hemaglutinin and neuraminidase, but will lose efficacy as soon as these proteins change (gradually or even in a single step). The latter process is known to continuously occur in nature.
In their attempts to make current strain-specific vaccines effective, the World Health Organization (WHO) has to annually predict the most likely viral strains that will be responsible for the next seasonal flu outbreak. This process takes place just a few months before flu season starts. This process is error prone, that is, it is possible that the vaccine may be manufactured against non-matching viral strains and not the one that may actually cause the epidemic. Moreover, as long as vaccines remain to be strain specific, it will be impossible to both manufacture them in advance and to enable their stockpiling. This, in turn, drives up the vaccine cost and makes its efficient world-wide distribution almost impossible.
Finally, the new strains of flu virus usually emerge in Asia and then migrate to Europe and North America. Recently, Indonesia demonstrated its reluctance to cooperate with WHO and restricted information exchange regarding the nature of a novel influenza strain. Several other countries in the region were sympathetic to Indonesia's actions. These and many other problems will never be fully resolved until anti-flu vaccines cease to be strain-specific.
However, all of the problems mentioned above could be alleviated by the development of a new generation of vaccine. Such a vaccine should be based on conserved flu proteins, which to a significant degree remain constant among all flu strains.
In addition to continuously mutating proteins, flu virus also possesses nucleoprotein (NP), and major matrix protein (M1), that reside inside the viral particle, and do not generate a strong antibody response. This may be the reason why these proteins do not naturally undergo significant mutagenesis and posses a striking degree of similarity among all influenza strains. Another conserved flu protein that is strongly expressed in virus-infected cells is a nonstructural protein 1 (NS1).
In the March issue of the scientific journal "Influenza and Other Respiratory Viruses", Massachusetts-based biotech company Cure Lab, Inc. reported that vaccinating mice with a combination of genes encoding these three conserved proteins of flu virus, NP, M1 and NS1, protected mice against human as well as avian strains of flu virus. In particular, this included an experiment demonstrating protection against bird flu virus that encodes type 5 hemaglutinin or H5. The challenge with this viral strain was used as a model of potential pandemic outbreak, which many believe may be caused by spreading of avian H5N1 virus to the human population. Moreover, in the same paper, Cure Lab reported that the same combination of three conserved viral genes provided significant protection against H5-carrying influenza strain in the chicken model.
In addition to Cure Lab, several other companies are also pursuing attempts to utilize genes encoding conserved flu proteins as vaccine components. This includes the California-based company Vical, known for its chemical adjuvant Vaxfectin. Vical included another extremely conserved flu protein, M2 into its proposed anti-flu product. M2 is present in low copy numbers at the surface of influenza viral particles, but is expressed abundantly on the surface of infected cells. Most of the research groups, including British biotech company, Acambis, have attempted to utilize only an extracellular domain of M2 protein called M2e. Despite some encouraging results demonstrating that if used at very high doses, M2e may induce a protective antibody response, the current opinion in the field is that it should be used only as a supplement to more potent antigens. One of the reasons may be that M2e lacks possible protective epitopes located within the intracellular and trans-membrane parts of M2. In addition, at least one recent report demonstrated that vaccination with M2e-encoding gene used in combination with the NP gene, exacerbated disease and increased mortality in pigs. In contrast to the Acambis strategy, Vical has included the gene encoding a full-size M2 into its vaccine prototype. The company reported that it had initiated clinical trials already.
"As it often happens, path-finding research starts as a result of an unexpected failure," said Dr. Alex Shneider, the senior author on the PLoS ONE paper and Cure Lab's CEO. "Initially, we believed that simply adding a gene encoding the full size M2 to our previously developed vaccine prototype would further increase the protective properties of the vaccine. Instead, we observed exactly the opposite".
Puzzled with such a counterintuitive result, Cure Lab went from product development to a basic science approach and asked the question: "Why would M2 decrease the efficiency of influenza vaccination?" Interestingly, for a number of years M2 was known to be insufficiently immunogenic in vaccine studies, which in fact, necessitated the utilization either of high doses of M2 or the shift to M2e-peptide as mentioned above. Earlier, Cure Lab demonstrated that M2 on its own may kill the cells producing this protein (uninfected with influenza). The scientists hypothesized that this is the underlying reason for the undesirable effect of M2 on vaccination. If this assumption was correct, then it would immediately suggest how to resolve the problem.
In order for M2 not to be able to exercise its negative functions, the protein should be "trapped" or neutralized in such a manner that prevents it from cell killing. Therefore, Cure Lab fused M2 with other proteins constituting a vaccine in such a way that NP, M1 and NS1 proteins restrict M2 functionality. This specific composite poly-protein, which did not kill the host cells, was selected based on its biochemical properties and cell-based assays.
Further animal testing demonstrated that the fusion construct containing all four conserved influenza proteins including "neutralized" M2, possesses much more promising protective properties than the same poly-protein without M2. "It shows us that the M2-gene can indeed be a valuable component of a novel anti-influenza vaccine if its negative effect is eliminated. One such approach is delineated in the PLoS ONE publication. Other possibilities are prevention of M2-induced cell death by introduction of specific mutations into the M2 gene or combining vaccination with drugs targeting M2, for example, amantadine"- said Dr. Alex Shneider.
"Our data does not necessarily indicate that clinical trials of vaccines utilizing genes encoding a full-size influenza M2 protein is unsafe" - stated Dr. Petr Ilyinskii, Principal Scientist at Cure Lab. "At the same time, it may suggest that the efficacy of M2-containing vaccines is not optimal for clinical trials and medical applications".
Meanwhile, pandemic flu continues to be one of the major threats to society. It remains to be seen whether it will be eliminated through the development of novel vaccines similarly to smallpox and polio or, at least, becomes controllable.
Public Library of Science
In their attempts to make current strain-specific vaccines effective, the World Health Organization (WHO) has to annually predict the most likely viral strains that will be responsible for the next seasonal flu outbreak. This process takes place just a few months before flu season starts. This process is error prone, that is, it is possible that the vaccine may be manufactured against non-matching viral strains and not the one that may actually cause the epidemic. Moreover, as long as vaccines remain to be strain specific, it will be impossible to both manufacture them in advance and to enable their stockpiling. This, in turn, drives up the vaccine cost and makes its efficient world-wide distribution almost impossible.
Finally, the new strains of flu virus usually emerge in Asia and then migrate to Europe and North America. Recently, Indonesia demonstrated its reluctance to cooperate with WHO and restricted information exchange regarding the nature of a novel influenza strain. Several other countries in the region were sympathetic to Indonesia's actions. These and many other problems will never be fully resolved until anti-flu vaccines cease to be strain-specific.
However, all of the problems mentioned above could be alleviated by the development of a new generation of vaccine. Such a vaccine should be based on conserved flu proteins, which to a significant degree remain constant among all flu strains.
In addition to continuously mutating proteins, flu virus also possesses nucleoprotein (NP), and major matrix protein (M1), that reside inside the viral particle, and do not generate a strong antibody response. This may be the reason why these proteins do not naturally undergo significant mutagenesis and posses a striking degree of similarity among all influenza strains. Another conserved flu protein that is strongly expressed in virus-infected cells is a nonstructural protein 1 (NS1).
In the March issue of the scientific journal "Influenza and Other Respiratory Viruses", Massachusetts-based biotech company Cure Lab, Inc. reported that vaccinating mice with a combination of genes encoding these three conserved proteins of flu virus, NP, M1 and NS1, protected mice against human as well as avian strains of flu virus. In particular, this included an experiment demonstrating protection against bird flu virus that encodes type 5 hemaglutinin or H5. The challenge with this viral strain was used as a model of potential pandemic outbreak, which many believe may be caused by spreading of avian H5N1 virus to the human population. Moreover, in the same paper, Cure Lab reported that the same combination of three conserved viral genes provided significant protection against H5-carrying influenza strain in the chicken model.
In addition to Cure Lab, several other companies are also pursuing attempts to utilize genes encoding conserved flu proteins as vaccine components. This includes the California-based company Vical, known for its chemical adjuvant Vaxfectin. Vical included another extremely conserved flu protein, M2 into its proposed anti-flu product. M2 is present in low copy numbers at the surface of influenza viral particles, but is expressed abundantly on the surface of infected cells. Most of the research groups, including British biotech company, Acambis, have attempted to utilize only an extracellular domain of M2 protein called M2e. Despite some encouraging results demonstrating that if used at very high doses, M2e may induce a protective antibody response, the current opinion in the field is that it should be used only as a supplement to more potent antigens. One of the reasons may be that M2e lacks possible protective epitopes located within the intracellular and trans-membrane parts of M2. In addition, at least one recent report demonstrated that vaccination with M2e-encoding gene used in combination with the NP gene, exacerbated disease and increased mortality in pigs. In contrast to the Acambis strategy, Vical has included the gene encoding a full-size M2 into its vaccine prototype. The company reported that it had initiated clinical trials already.
"As it often happens, path-finding research starts as a result of an unexpected failure," said Dr. Alex Shneider, the senior author on the PLoS ONE paper and Cure Lab's CEO. "Initially, we believed that simply adding a gene encoding the full size M2 to our previously developed vaccine prototype would further increase the protective properties of the vaccine. Instead, we observed exactly the opposite".
Puzzled with such a counterintuitive result, Cure Lab went from product development to a basic science approach and asked the question: "Why would M2 decrease the efficiency of influenza vaccination?" Interestingly, for a number of years M2 was known to be insufficiently immunogenic in vaccine studies, which in fact, necessitated the utilization either of high doses of M2 or the shift to M2e-peptide as mentioned above. Earlier, Cure Lab demonstrated that M2 on its own may kill the cells producing this protein (uninfected with influenza). The scientists hypothesized that this is the underlying reason for the undesirable effect of M2 on vaccination. If this assumption was correct, then it would immediately suggest how to resolve the problem.
In order for M2 not to be able to exercise its negative functions, the protein should be "trapped" or neutralized in such a manner that prevents it from cell killing. Therefore, Cure Lab fused M2 with other proteins constituting a vaccine in such a way that NP, M1 and NS1 proteins restrict M2 functionality. This specific composite poly-protein, which did not kill the host cells, was selected based on its biochemical properties and cell-based assays.
Further animal testing demonstrated that the fusion construct containing all four conserved influenza proteins including "neutralized" M2, possesses much more promising protective properties than the same poly-protein without M2. "It shows us that the M2-gene can indeed be a valuable component of a novel anti-influenza vaccine if its negative effect is eliminated. One such approach is delineated in the PLoS ONE publication. Other possibilities are prevention of M2-induced cell death by introduction of specific mutations into the M2 gene or combining vaccination with drugs targeting M2, for example, amantadine"- said Dr. Alex Shneider.
"Our data does not necessarily indicate that clinical trials of vaccines utilizing genes encoding a full-size influenza M2 protein is unsafe" - stated Dr. Petr Ilyinskii, Principal Scientist at Cure Lab. "At the same time, it may suggest that the efficacy of M2-containing vaccines is not optimal for clinical trials and medical applications".
Meanwhile, pandemic flu continues to be one of the major threats to society. It remains to be seen whether it will be eliminated through the development of novel vaccines similarly to smallpox and polio or, at least, becomes controllable.
Public Library of Science
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