Intranasal Vaccine for Noroviral Infections in Pipeline

CHICAGO – An intranasal vaccine reduces norovirus disease and infection in humans, results from a proof-of-concept study suggest.

The findings are important because infections with norovirus, commonly referred to as "cruise ship viruses," cause 96% of all nonbacterial outbreaks of gastroenteritis, Mary K. Estes, Ph.D., said during the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

"These viruses are highly contagious and affect all age groups," said Dr. Estes, who directs the Texas Medical Center Digestive Diseases Center in Houston. "They are known to be the leading cause of viral gastroenteritis and outbreaks worldwide, and their impact is increasingly being recognized."

In the United States, she said, norovirus infections causes 12% of severe gastroenteritis cases among children younger than 5 years of age, 64,000 hospitalizations, and 900,000 pediatric clinic visits. "With the significant impact of the new rotavirus vaccines, noroviruses are now emerging as the primary cause of gastroenteritis in hospitalized children," Dr. Estes said. "They are also recognized now to be causing excess deaths in the elderly. In the developing world, they’re estimated to cause about 200,000 deaths each year."

"This is the first demonstration that an intranasally-delivered vaccine can prevent human illness due to an enteric pathogen."

A chief obstacle to developing a vaccine for norovirus includes the lack of an in vitro culture system. "We still can’t grow these viruses yet, although they grow very well in people," Dr. Estes explained. "There is no readily available relevant animal model, and there is antigenic and genetic diversity of noroviruses."

The two main genogroups of noroviruses in humans include genogroup 1, which is comprised of nine clusters (including the Norwalk virus), and genogroup 2, which is comprised of 19 different clusters. "These are the viruses that are most commonly associated with outbreaks," she said. "Ultimately, we probably will at least need a bivalent vaccine to protect against these viruses in the different groups."

Using challenge models in humans, researchers have discovered that norovirus affects secreter positive individuals while nonsecreters, who lack a functioning FUT2 gene, are resistant to norovirus infection.

Dr. Estes presented results from a randomized trial of a baculovirus-expressed norovirus vaccine made by Bozeman (Ligocyte Pharmaceuticals).

The randomized study took place in two stages at four clinical sites. In the first stage, 98 secretor-positive volunteers between the ages of 18 and 50 were given either vaccine or placebo (10 mcg of Norwalk virus-like particles). In stage two, 84 of the volunteers were challenged with the virus to see if infection or disease could be prevented. The primary objective of the study was to evaluate vaccine safety as measured by frequency of viral acute gastroenteritis (AGE). Secondary objectives were to determine efficacy as measured by infection frequency, AGE severity and duration, viral antigen and RNA shedding, vaccine immunogenicity, and vaccine safety.

Study participants were randomized to a two-dose regimen 3 weeks apart: 100 mcg of norovirus virus-like particles or placebo intranasally. They were challenged with 10 human infectious doses at 50% of the challenge virus.

The researchers established three definitions for AGE: greater than 200 g watery diarrhea within 24 hours, vomiting plus any watery diarrhea, and vomiting plus at least one constitutional symptom.

Viral infection was monitored by virus fecal shedding by antigen or real-time polymerase chain reaction testing as well as a rise in antibody levels from pre- to post-challenge.

Dr. Estes reported that the intranasal vaccine was well tolerated, with no vaccine-related severe adverse events or new onset of medically significant conditions. There were two unrelated hospitalizations: one for appendectomy and one for anxiety.

The percentage of subjects with a fourfold or greater rise of total antibodies after the second dose was 62% in vaccine group versus 2% in placebo group, while the percentage with a fourfold or greater rise of IgA antibody after the second dose was 64% in vaccine group versus 2% in the placebo group.

"Noroviruses are now emerging as the primary cause of gastroenteritis in hospitalized children."

In the intent-to-treat analysis, 40% of subjects in the vaccine group had AGE vs. 71% of subjects in the placebo group, for a reduction of 44%. The numbers were similar in the per protocol analysis, which demonstrated that 37% of subjects in the vaccine group had AGE versus 69% in the placebo group, for a reduction of 47%.

In the intent-to-treat analysis, norovirus infection occurred in 65% of the vaccine group versus. 83% of the placebo group, for nonsignificant reduction of 22%.

In the per-protocol analysis, norovirus infection occurred in 61% in the vaccine group versus 82% in the placebo group, for a significant reduction of 26%.

"From this study, we can conclude that the intranasally administered norovirus vaccine was immunogenic in about two-thirds of subjects," Dr. Estes said at the meeting, which was sponsored by the American Society for Microbiology. "The vaccine protected against illness in both analyses and decreased infection per protocol only. Protection in this vaccine study also correlated with histo-blood group antigen blocking titer 50%. This is the first demonstration that an intranasally-delivered vaccine can prevent human illness due to an enteric pathogen."

She pointed out that several questions about the vaccine remain unanswered, including its duration of protection and whether or not immunogenicity can be improved. "We need to evaluate different routes of administration, schedules, dosages, and adjuvants," she added.

Dr. Estes disclosed that she is a consultant for Ligocyte Pharmaceuticals. She has also received royalties from Denka Seiken Diagnostics of Tokyo.

CHICAGO – An intranasal vaccine reduces norovirus disease and infection in humans, results from a proof-of-concept study suggest.

The findings are important because infections with norovirus, commonly referred to as "cruise ship viruses," cause 96% of all nonbacterial outbreaks of gastroenteritis, Mary K. Estes, Ph.D., said during the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

"These viruses are highly contagious and affect all age groups," said Dr. Estes, who directs the Texas Medical Center Digestive Diseases Center in Houston. "They are known to be the leading cause of viral gastroenteritis and outbreaks worldwide, and their impact is increasingly being recognized."

In the United States, she said, norovirus infections causes 12% of severe gastroenteritis cases among children younger than 5 years of age, 64,000 hospitalizations, and 900,000 pediatric clinic visits. "With the significant impact of the new rotavirus vaccines, noroviruses are now emerging as the primary cause of gastroenteritis in hospitalized children," Dr. Estes said. "They are also recognized now to be causing excess deaths in the elderly. In the developing world, they’re estimated to cause about 200,000 deaths each year."

"This is the first demonstration that an intranasally-delivered vaccine can prevent human illness due to an enteric pathogen."

A chief obstacle to developing a vaccine for norovirus includes the lack of an in vitro culture system. "We still can’t grow these viruses yet, although they grow very well in people," Dr. Estes explained. "There is no readily available relevant animal model, and there is antigenic and genetic diversity of noroviruses."

The two main genogroups of noroviruses in humans include genogroup 1, which is comprised of nine clusters (including the Norwalk virus), and genogroup 2, which is comprised of 19 different clusters. "These are the viruses that are most commonly associated with outbreaks," she said. "Ultimately, we probably will at least need a bivalent vaccine to protect against these viruses in the different groups."

Using challenge models in humans, researchers have discovered that norovirus affects secreter positive individuals while nonsecreters, who lack a functioning FUT2 gene, are resistant to norovirus infection.

Dr. Estes presented results from a randomized trial of a baculovirus-expressed norovirus vaccine made by Bozeman (Ligocyte Pharmaceuticals).

The randomized study took place in two stages at four clinical sites. In the first stage, 98 secretor-positive volunteers between the ages of 18 and 50 were given either vaccine or placebo (10 mcg of Norwalk virus-like particles). In stage two, 84 of the volunteers were challenged with the virus to see if infection or disease could be prevented. The primary objective of the study was to evaluate vaccine safety as measured by frequency of viral acute gastroenteritis (AGE). Secondary objectives were to determine efficacy as measured by infection frequency, AGE severity and duration, viral antigen and RNA shedding, vaccine immunogenicity, and vaccine safety.

Study participants were randomized to a two-dose regimen 3 weeks apart: 100 mcg of norovirus virus-like particles or placebo intranasally. They were challenged with 10 human infectious doses at 50% of the challenge virus.

The researchers established three definitions for AGE: greater than 200 g watery diarrhea within 24 hours, vomiting plus any watery diarrhea, and vomiting plus at least one constitutional symptom.

Viral infection was monitored by virus fecal shedding by antigen or real-time polymerase chain reaction testing as well as a rise in antibody levels from pre- to post-challenge.

Dr. Estes reported that the intranasal vaccine was well tolerated, with no vaccine-related severe adverse events or new onset of medically significant conditions. There were two unrelated hospitalizations: one for appendectomy and one for anxiety.

The percentage of subjects with a fourfold or greater rise of total antibodies after the second dose was 62% in vaccine group versus 2% in placebo group, while the percentage with a fourfold or greater rise of IgA antibody after the second dose was 64% in vaccine group versus 2% in the placebo group.

"Noroviruses are now emerging as the primary cause of gastroenteritis in hospitalized children."

In the intent-to-treat analysis, 40% of subjects in the vaccine group had AGE vs. 71% of subjects in the placebo group, for a reduction of 44%. The numbers were similar in the per protocol analysis, which demonstrated that 37% of subjects in the vaccine group had AGE versus 69% in the placebo group, for a reduction of 47%.

In the intent-to-treat analysis, norovirus infection occurred in 65% of the vaccine group versus. 83% of the placebo group, for nonsignificant reduction of 22%.

In the per-protocol analysis, norovirus infection occurred in 61% in the vaccine group versus 82% in the placebo group, for a significant reduction of 26%.

"From this study, we can conclude that the intranasally administered norovirus vaccine was immunogenic in about two-thirds of subjects," Dr. Estes said at the meeting, which was sponsored by the American Society for Microbiology. "The vaccine protected against illness in both analyses and decreased infection per protocol only. Protection in this vaccine study also correlated with histo-blood group antigen blocking titer 50%. This is the first demonstration that an intranasally-delivered vaccine can prevent human illness due to an enteric pathogen."

She pointed out that several questions about the vaccine remain unanswered, including its duration of protection and whether or not immunogenicity can be improved. "We need to evaluate different routes of administration, schedules, dosages, and adjuvants," she added.

Dr. Estes disclosed that she is a consultant for Ligocyte Pharmaceuticals. She has also received royalties from Denka Seiken Diagnostics of Tokyo.

CHICAGO – An intranasal vaccine reduces norovirus disease and infection in humans, results from a proof-of-concept study suggest.

The findings are important because infections with norovirus, commonly referred to as "cruise ship viruses," cause 96% of all nonbacterial outbreaks of gastroenteritis, Mary K. Estes, Ph.D., said during the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

"These viruses are highly contagious and affect all age groups," said Dr. Estes, who directs the Texas Medical Center Digestive Diseases Center in Houston. "They are known to be the leading cause of viral gastroenteritis and outbreaks worldwide, and their impact is increasingly being recognized."

In the United States, she said, norovirus infections causes 12% of severe gastroenteritis cases among children younger than 5 years of age, 64,000 hospitalizations, and 900,000 pediatric clinic visits. "With the significant impact of the new rotavirus vaccines, noroviruses are now emerging as the primary cause of gastroenteritis in hospitalized children," Dr. Estes said. "They are also recognized now to be causing excess deaths in the elderly. In the developing world, they’re estimated to cause about 200,000 deaths each year."

"This is the first demonstration that an intranasally-delivered vaccine can prevent human illness due to an enteric pathogen."

A chief obstacle to developing a vaccine for norovirus includes the lack of an in vitro culture system. "We still can’t grow these viruses yet, although they grow very well in people," Dr. Estes explained. "There is no readily available relevant animal model, and there is antigenic and genetic diversity of noroviruses."

The two main genogroups of noroviruses in humans include genogroup 1, which is comprised of nine clusters (including the Norwalk virus), and genogroup 2, which is comprised of 19 different clusters. "These are the viruses that are most commonly associated with outbreaks," she said. "Ultimately, we probably will at least need a bivalent vaccine to protect against these viruses in the different groups."

Using challenge models in humans, researchers have discovered that norovirus affects secreter positive individuals while nonsecreters, who lack a functioning FUT2 gene, are resistant to norovirus infection.

Dr. Estes presented results from a randomized trial of a baculovirus-expressed norovirus vaccine made by Bozeman (Ligocyte Pharmaceuticals).

The randomized study took place in two stages at four clinical sites. In the first stage, 98 secretor-positive volunteers between the ages of 18 and 50 were given either vaccine or placebo (10 mcg of Norwalk virus-like particles). In stage two, 84 of the volunteers were challenged with the virus to see if infection or disease could be prevented. The primary objective of the study was to evaluate vaccine safety as measured by frequency of viral acute gastroenteritis (AGE). Secondary objectives were to determine efficacy as measured by infection frequency, AGE severity and duration, viral antigen and RNA shedding, vaccine immunogenicity, and vaccine safety.

Study participants were randomized to a two-dose regimen 3 weeks apart: 100 mcg of norovirus virus-like particles or placebo intranasally. They were challenged with 10 human infectious doses at 50% of the challenge virus.

The researchers established three definitions for AGE: greater than 200 g watery diarrhea within 24 hours, vomiting plus any watery diarrhea, and vomiting plus at least one constitutional symptom.

Viral infection was monitored by virus fecal shedding by antigen or real-time polymerase chain reaction testing as well as a rise in antibody levels from pre- to post-challenge.

Dr. Estes reported that the intranasal vaccine was well tolerated, with no vaccine-related severe adverse events or new onset of medically significant conditions. There were two unrelated hospitalizations: one for appendectomy and one for anxiety.

The percentage of subjects with a fourfold or greater rise of total antibodies after the second dose was 62% in vaccine group versus 2% in placebo group, while the percentage with a fourfold or greater rise of IgA antibody after the second dose was 64% in vaccine group versus 2% in the placebo group.

"Noroviruses are now emerging as the primary cause of gastroenteritis in hospitalized children."

In the intent-to-treat analysis, 40% of subjects in the vaccine group had AGE vs. 71% of subjects in the placebo group, for a reduction of 44%. The numbers were similar in the per protocol analysis, which demonstrated that 37% of subjects in the vaccine group had AGE versus 69% in the placebo group, for a reduction of 47%.

In the intent-to-treat analysis, norovirus infection occurred in 65% of the vaccine group versus. 83% of the placebo group, for nonsignificant reduction of 22%.

In the per-protocol analysis, norovirus infection occurred in 61% in the vaccine group versus 82% in the placebo group, for a significant reduction of 26%.

"From this study, we can conclude that the intranasally administered norovirus vaccine was immunogenic in about two-thirds of subjects," Dr. Estes said at the meeting, which was sponsored by the American Society for Microbiology. "The vaccine protected against illness in both analyses and decreased infection per protocol only. Protection in this vaccine study also correlated with histo-blood group antigen blocking titer 50%. This is the first demonstration that an intranasally-delivered vaccine can prevent human illness due to an enteric pathogen."

She pointed out that several questions about the vaccine remain unanswered, including its duration of protection and whether or not immunogenicity can be improved. "We need to evaluate different routes of administration, schedules, dosages, and adjuvants," she added.

Dr. Estes disclosed that she is a consultant for Ligocyte Pharmaceuticals. She has also received royalties from Denka Seiken Diagnostics of Tokyo.