a SLACK Incorporated newspaper
December 1998
The past year saw a wealth of news surrounding vaccines. Some of the biggest news in the industry for 1998 was the approval of the first vaccine for protection against rotavirus gastroenteritis (RotaShield, Wyeth-Lederle Vaccines) and its anticipated addition to the harmonized childhood immunization schedule for 1999.
A second vaccine also received FDA approval during 1998. The fourth acellular pertussis vaccine (Certiva, North American Vaccine) was approved in July for routine use in children.
A Lyme disease vaccine (LYMErix, SmithKline Beecham) was recommended for approval in May by the Vaccines and Related Biological Products Advisory Committee of the Food and Drug Administration (FDA). A live, oral cholera vaccine (Mutacol Berna, Swiss Serum and Vaccine Institute) was also reviewed by the FDA advisory panel in May but was not recommended for approval.
Two additional pediatric vaccines received much attention in 1998: an intranasal influenza vaccine (FluMist, Aviron) and a pneumococcal vaccine (Wyeth-Lederle Vaccines).
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The oral, tetravalent rotavirus vaccine was approved by the FDA in August and is indicated for the primary series in infants at 2, 4 and 6 months of age. An October vote by the Advisory Committee on Immunization Practices (ACIP) added the vaccine to the 1999 childhood immunization schedule. The harmonized schedule of recommendations by the ACIP, American Academy of Pediatrics (AAP) and American Academy of Family Physicians, is expected to reflect the same recommendation and will be available in January 1999.
This vaccine is the first new pediatric vaccine approved for routine use since 1995.
Rotavirus is the most common cause of severe acute gastroenteritis in infants and young children worldwide. Rota virus is responsible for 30% to 50% of all diarrheal hospitalizations for children younger than 5 years.
Studies have shown that each year rotavirus infects 2.7 million U.S. children, 500,000 of those are seen by a physician and 50,000 are hospitalized, for a total cost to society reaching $1.4 billion. Experts estimate that an immunization program may prevent 1.08 million cases of diarrhea, avoiding 34,000 hospitalizations, 95,000 emergency department visits and 227,000 physician visits among children 5 years and younger.
As with most newly approved vaccines, the biggest challenge is educating parents and providers about the disease and the vaccine. An education program is being developed because many providers and parents are unfamiliar with rotavirus, said rotavirus researcher Joseph Bresee, MD, Viral Gastroenteritis Section of the Centers for Disease Control and Prevention (CDC).
"There's nothing more important than getting the message out that this is an important vaccine-preventable disease and we now have a vaccine we can use, and will soon have recommendations on how to use it. Then we have to convince practitioners and parents that the vaccine is really useful," Bresee said.
An important part of the education is that diarrhea may still occur after vaccination with rotavirus vaccine, but it will be less severe. Therefore, parents must be informed that the vaccine does not prevent all diarrheal episodes. "Parents must be told that this vaccine has a good chance of preventing the most common cause of severe diarrhea that nearly every child is going to get. But, there's a lot of causes of diarrhea and they all look the same to parents," he added.
Acceptance of the vaccine among physicians will depend on their exposure to children with the disease, explained Larry K. Pickering, MD, director of the Center for Pediatric Research in Norfolk, Va., and a member of the Infectious Diseases in Children editorial board.
"I think it's going to depend on the experience of the physician, and because of that it's going to take some time to educate all physicians that this is an important vaccine," said Pickering, editor of the AAP 2000 Red Book. "The good thing about the vaccine is that it's oral and doesn't add to the pin-cushion effect."
Each dose of the three-dose series sold in the United States costs $38, said Doug Petkus, spokesman for Wyeth-Lederle Vaccines.
North American Vaccine received approval for CERTIVA, which uses a monocomponent (pertussis toxoid) acellular pertussis vaccine developed in the National Institute of Child Health and Human Development (NICHD) laboratory of John Robbins, MD. The NICHD licensed its patent for producing this pertussis vaccine to North American Vaccine.
The vaccine is indicated for the primary series at 2, 4 and 6 months, with a booster dose at 15-18 months. If a child has received one or more doses of whole-cell pertussis vaccine, CERTIVA can be given to complete the five-dose series, said Stephen Keith, MD, vice president of marketing and sales at North American Vaccine.
This DTaP vaccine differs from the other licensed DTaP vaccines because it consists of a single antigen, pertussis toxoid, which is pure pertussis toxin detoxified by hydrogen peroxide. The other acellular pertussis vaccines contain multiple pertussis antigens and prepare pertussis toxoid differently.
The U.S. clinical studies, sponsored by North American Vaccine, the NICHD and the National Institute of Allergy and Infectious Diseases (NIAID), involved 3,715 healthy infants and children in study sites across the United States. One safety and efficacy study involved 1,303 infants who randomly received CERTIVA or a licensed whole-cell pertussis vaccine.
Most of these infants were immunized concurrently with other routinely administered childhood vaccines. The incidence of fever, redness, pain, irritability and swelling were all significantly lower after vaccination with CERTIVA than after immunization with the whole-cell vaccine.
The most common adverse events reported during the studies were irritability and redness and pain at the injection site. CERTIVA has also been given as the fourth and fifth doses in clinical studies and was well tolerated and immunogenic.
An ongoing mass vaccine project in Göteborg, Sweden, under which 50,000 infants and young children have received the same pertussis toxoid as is contained in CERTIVA, formulated as DTaP or aP, has lead to a very significant reduction in the incidence of pertussis in the community, among vaccinees and non vaccinees of all ages. These data also demonstrate the possibility of eliminating pertussis by vaccination with a single component of Bordetella pertussis, Robbins added.
CERTIVA will be marketed and distributed by the Ross Products Division of Abbott Laboratories Inc. to private physicians and managed care markets and by North American Vaccine to government purchasers.
The FDA Vaccines and Related Biological Products Advisory Committee in May voted unanimously that a Lyme disease vaccine manufactured by Smith Kline Beecham Biologicals is safe and efficacious.
In three unanimous votes, the FDA advisory committee agreed that the vaccine, LYMErix (recombinant Borrelia burgdorferi [L-OspA] vaccine), is safe for immunization of individuals 15 to 70 years of age. The panel also agreed that the vaccine appeared effective against definite Lyme disease in those 15-70 years after receiving vaccine at zero, one month and 12 months. In the final vote, the committee recommended a similar seasonal vaccination schedule used in the trial be included in the package insert.
The committee was cautious, however, and stated several provisions before agreeing that the data presented demonstrated safety and efficacy. Provisos proposed by the committee included expanding the age groups studied; studies in patients with arthritis; longer follow-up; studies of the impact of booster doses; and investigating further the possibility of chronic sequelae.
The multicenter, double-blind, randomized trial involved more than 10,000 volunteers age 15-70 years who received either three doses of vaccine or placebo. Thirteen volunteers in the vaccine group tested positive for definite Lyme disease, compared with 61 in the placebo group.
Following the completion of the three-dose series, the vaccine was 79% effective in patients 15-70 years of age with definite Lyme disease. For patients the same age with asymptomatic infection, the vaccine was 100% effective, according to the study results.
Approximately 15% to 30% of cases are asymptomatic in the initial period following infection.
Safety concerns surrounding the vaccine focused on the risk of arthralgia; therefore, committee members expressed the need for additional safety and immunogenicity data.
Patricia L. Ferrieri, MD, professor, departments of laboratory medicine and pathology, and pediatrics, University of Minnesota Medical School, Minneapolis and director of the clinical microbiology laboratory suggested a subtrial of patients with chronic arthritis or joint disease and long-term follow-ups be conducted, as well as further investigation into booster doses because only 50% efficacy was demonstrated during the first year.
LYMErix was generally well tolerated; the most common side effect was a local reaction at the injection site.
The ACIP also reviewed the clinical data for Lyme disease vaccine and is preparing a statement for the vaccine's use. The consensus of the committee was that the recommendation should not be for universal use, but rather a risk-based recommendation.
Pasteur Mérieux Connaught has also submitted an application to the FDA for approval of its Lyme disease vaccine.
The FDA advisory committee did not look as favorably upon cholera vaccine as it did the Lyme disease vaccine. The committee reviewed safety and efficacy data for the live, oral CVD103-HgR vaccine (Mutacol Berna, Swiss Serum and Vaccine Institute) indicated for travelers from industrialized countries to cholera-endemic areas.
This was the second FDA committee review of the vaccine; the first review was in 1993.
The advisory committee did vote unanimously that volunteer challenge studies could demonstrate efficacy of the vaccine in the prevention of cholera in U.S. travelers to cholera-affected areas, but that the challenge studies presented did not demonstrate the appropriate efficacy results.
"If one looks at the safety and efficacy profile of the licensed vaccine, most of us would be reluctant to advise patients to get this vaccine because of the very high rate of reactogenicity, the need for two doses and the extremely short duration of minimal protection," said committee member Mary Lou Clements-Mann, MD, MPH, during a May FDA advisory committee meeting. Clements-Mann was a professor in the departments of international health, molecular microbiology and immunology, and medicine at Johns Hopkins University, Baltimore.
The proposed indication of the vaccine was for individuals 2 years and older who are traveling to cholera-endemic areas, and was not proposed for routine administration.
The committee voted that the challenge studies were not designed and executed adequately. Two major concerns were mentioned regarding the data presented: the short duration of immunity and level of risk.
The CVD103-HgR vaccine is licensed for use in Canada and in several European countries, and 40,000 doses were distributed between 1994-1996.
An experimental vaccine for the prevention of pneumococcal disease in children was shown 100% effective in a trial of more than 38,000 children 15 months and younger. The pneumococcal conjugate vaccine was effective in preventing bacterial meningitis and bacteremia caused by Streptococcus pneumoniae.
he three-year clinical trial of the seven-valent vaccine was conducted at 23 Kaiser Permanente sites in northern California by Henry Shinefield, MD, and Steven Black, MD, a member of the Infectious Diseases in Childreneditorial board. Because of the favorable results, the trial ended ahead of schedule.
"We have stopped the study and will vaccinate children in the control group," Shinefield said.
The seven strains included in the vaccine cause approximately 85% of the pneumococcal disease reported in the United States.
During the randomized, double-blind study, half the infants received the pneumococcal conjugate vaccine and half received the control vaccine, which was a protein conjugate of the meningococcal polysaccharide type C. Each child was given doses at 2, 4 and 6 months of age and a booster at 12-15 months.
Between October 1995 and August 1998, 22 cases of invasive pneumococcal disease caused by one of the vaccine strains were identified; however, none were reported in the vaccine group. "Seventeen cases were in the fully immunized control group and five were in the partially immunized control group," Shinefield said. "The data is highly significant, both in completed vaccinations and the intent to treat group, as well."
There was no evidence of increased disease due to the strains not covered by the vaccine, Shinefield added.
Data from the study will be further analyzed to determine the vaccine's effectiveness against otitis media and pneumonia and the cost effectiveness of vaccinating all U.S. children. The company anticipates filing a product license application for the vaccine no later than the first quarter in 1999, Petkus said.
Efficacy results for the new intranasal influenza vaccine were similarly impressive. Data from the second year of a phase 3 efficacy trial in children show that Aviron's FluMist intranasal influenza virus vaccine provided 100% protection against culture-confirmed influenza strains included in last year's flu vaccine, and 86% protection against the predominant strain of influenza circulating during last year's flu season, influenza A/Sydney strain.
The influenza A/Sydney strain was not included in the 1997-98 formulation because FluMist was designed to match the flu shot marketed that year; the flu shot was not studied in this trial.
"Live-attenuated virus vaccines such as FluMist are thought to mimic natural infection better than other types of vaccines. In addition, FluMist is delivered to the upper airway, the natural port of entry for the influenza virus," said lead investigator Robert Belshe, MD, director of infectious diseases and immunology, and director of the Center for Vaccine Development at Saint Louis University, St. Louis, Mo.
Results indicate that overall, FluMist provided 87% protection against all culture-confirmed influenza. In the 1,358 participants, five cases of influenza occurred due to influenza strains included in the vaccine and 66 cases were caused by A/Sydney.
Only 2% of children vaccinated with FluMist (15 out of 917) experienced culture-confirmed influenza, all of which was attributable to the A/Sydney strain, while 13% of the placebo recipients (56 of 441) experienced culture-confirmed influenza.
The difference between these two influenza attack rates is used to calculate the overall protection rate of 87%. The incidence of pneumonia and other lower respiratory diseases was also reduced, compared with placebo. Eight children in the placebo group developed influenza-related wheezing, bronchitis or pneumonia. All of these were due to the A/Sydney strain. No children who received FluMist experienced lower respiratory complications.
The children participated for a second flu season in the 1997-98 follow-up trial. They were either vaccinated with a single dose of FluMist or a placebo spray. Of the 15 children out of 917 children in the FluMist group who did contract influenza, the illness appeared to be milder than in the control group, based on frequency of complications and duration of fever. This double-blind, placebo-controlled trial was conducted at 10 sites nationwide in collaboration with the NIAID.
The new data also indicate that FluMist provided 94% protection against influenza-related otitis media (two cases in the vaccine group vs. 17 in the placebo group). Otitis media is the most common illness in young children requiring a doctor visit.
On Aug. 31, Aviron reported that it received notice from the FDA that its application was not accepted for filing due to a lack of data on manufacturing, validation and stability. Therefore, it is unlikely that FluMist will be available for the 1999-2000 flu season.
Aviron intends to seek U.S. licensure for FluMist to prevent influenza and its complications in children and adults.
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