Vaccines in the Pipeline -- An Overview-->medline转移

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Vaccines in the Pipeline -- An Overview Barbara Watson, MB, ChB, Albert Einstein Medical Center, Philadelphia [Infect Med 18(8s):FV27-FV32, 2001. © 2001 Cliggott Publishing Co., Division of SCP/Cliggott Communications, Inc.] Abstract and Introduction Abstract Vaccination is a highly effective preventive strategy, and some vaccines are true "success stories." These include vaccines against smallpox, diphtheria, poliomyelitis, measles, mumps, and rubella. Existing vaccines can be used more effectively for preventing influenza, hepatitis A, hepatitis B, meningococcal disease, pneumococcal infection, and varicella (including zoster). Of great promise are vaccines now in the development "pipeline." These include vaccines against cytomegalovirus infection, group B streptococcal disease, HIV disease, hepatitis C, rotavirus infection, pertussis in adolescents and adults, human papillomavirus infection, genital herpes, tuberculosis, malaria, meningococcal disease caused by serotype B organisms, and infection with multidrug-resistant staphylococci. A cold-adapted nasal influenza vaccine is close to approval. Immunization registries will enhance vaccine use rates. Improved delivery methods will augment effectiveness of vaccines. Introduction Vaccines are available for prevention of a number of diseases and have been highly successful in many instances (Table 1). Some diseases, such as smallpox, have in effect been eradicated from the planet. Improvements are needed in several areas, however. These include improvement in vaccine delivery, development of combination vaccines, and increasing the effectiveness and utilization rates of existing vaccines (Table 2). For a number of diseases that remain significant public health challenges throughout the United States and the rest of the world, vaccines have yet to be developed or made available (Table 3).[1] These much-needed vaccines, some of which are in clinical trials, are the focus of intensive research and will be the subject of this article. Cytomegalovirus Infection Infection with cytomegalovirus (CMV) is the leading cause of congenital deafness, blindness, mental retardation, and seizures secondary to primary maternal infection and accounts for disease in 40,000 infants per year in the United States.[1,2] Longitudinal studies of congenital infection demonstrating the protective effect of preconception maternal immunity stimulated interest in vaccine development 2 decades ago. Live attenuated CMV vaccine strains (Towne vaccine) have been tested. Phase I and II studies in renal transplant recipients demonstrated an 89% efficacy in preventing severe CMV disease.[1] In susceptible healthy mothers, however, the vaccine was ineffective. Current strategies to develop an effective vaccine are based on the use of glycoprotein (gp) subunits. Subunit vaccines currently in trials employ a modified glycoprotein B (gB), in a different adjuvant than used in the Towne vaccine. Phase I and II trials have demonstrated safety and immunogenicity as well as production of mucosal immunity.[3] Surrogate markers of protection need to be developed before phase III efficacy trials can be performed.[2] In addition, results of trials in which avipox (canarypox) was used as a vaccine vector alone or with the Towne vaccine to express the CMV gB suggest that a combined-vaccine approach could induce protective levels of neutralizing antibodies.[4] Group B streptococcal disease A vaccine against group B streptococci (GBS) is under development to prevent neonatal disease. Prenatal screening cultures for GBS and a risk-based strategy to identify women who should receive intrapartum penicillin prophylaxis have been reasonably successful in reducing rates of GBS disease, which declined from 1.7 per 1000 to 0.6 per 1000 during the 1990s.[5] Phase I and II studies of the vaccine, however, have demonstrated safety and immunogenicity and it is hoped that commitment can be found to bring these vaccines to licensure.[1,5-7] HIV Disease The first 2 decades of the AIDS epidemic witnessed improvement in quality of life through control of opportunistic infections and improvements in antiviral therapy. Vaccine development, however, has been impeded by the genetic diversity of HIV, inadequate knowledge of correlates of protection, and the need to evaluate both humoral and cellular immunity. A subunit vaccine, AIDSVAX, based on gp120 subunits, has been tested in 2 series of phase I and phase II trials.[8] In both series, AIDSVAX appears to be safe and produces antibodies in virtually everyone who receives it. In the first series, all vaccinated participants in phase II produced antibodies in blood that neutralized the HIV strain for which the vaccine was designed. In the second series, AIDSVAX was reformulated to include gp120 from 2 strains of HIV instead of 1. This bivalent vaccine appeared safe, and the magnitude and quality of the immune response was improved. On June 23, 1998, AIDSVAX was administered to the first volunteer in the world's first phase III trial of a preventive HIV/AIDS vaccine. Now, approximately 8000 participants are enrolled in 2 separate studies taking place on 3 continents.[1,9,10] In addition, a DNA vaccine is being developed that induces CD8[+] cytotoxic T lymphocytes and targets HIV subtype A, which is common in Africa.[1,11] A vaccine to induce cell-mediated immunity using canarypox as a vector and the gp120 subunit has completed phase II trials; phase III trials are expected.[1,11-13] Inactivated HIV vaccines, for the most part, are "prime-boost" regimens tailored to raise cellular immune responses against HIV. Priming is generally mediated by a "naked" DNA vector, while a viral vector is used for subsequent boosting. These are in early stages of clinical development. Some consist of HIV stripped of its envelope proteins, an example of which (Remune) is being assessed in clinical trials as a postexposure vaccine in combination with antiretroviral therapy.[1,11,12] Live attenuated HIV vaccines are also in development. Researchers are deleting genes thought to cause HIV disease from the viral genome and evaluating the immunogenic product in animal models. At least 9 different HIV vaccines are in development.[1,11,12] Hepatitis C Hepatitis C virus (HCV) is the most common cause of chronic blood-borne infection in the United States. The National Health and Nutrition Examination Survey estimates that 3.9 million persons have been infected.[14] Moreover, chronic liver disease is the 10th leading cause of death among adults in the United States, accounting for 25,000 deaths; 40% of these are HCV-related. Prevention options currently consist of interruption of transmission, identification of cases, counseling and testing persons at risk, and appropriate medical evaluation and management of infected individuals. HCV, however, is a very difficult target for prevention. Up to 80% of all persons who become infected with HCV become chronically infected. Only a minority appear to control and clear the infection. The first attempted HCV vaccine consisted of a recombinant DNA (rDNA)-derived envelope protein. Preliminary results in chimpanzees, the only useful model, reported in the mid-1990s were mixed. Several diverse approaches are currently under investigation, with no clear choice for a leading contender. Numerous candidate vaccines are at various stages of development, with only 1 being tested in the clinic. This candidate employs the envelope proteins E1 or E1 + E2, DNA, or yellow fever virus as the vector. Preliminary trials examining the immune correlates of infection are under way.[1,12] Rotavirus Infection Rotavirus, classified in the Reoviridae family, consists of 11 segments of double-stranded RNA, each encoding a single protein. Its outer shell contains 2 structural proteins, VP4 and VP7, which determine the serotype and are important for protective immunity. Rotavirus causes fever, vomiting, and diarrhea in children and immunocompromised persons. Rotavirus is a major cause of diarrhea. Complications of infection include dehydration, which is relatively common. Dehydration leads to approximately 1 out of every 75 children being treated in the hospital, and altogether rotavirus infection is responsible for some 55,000 hospitalizations annually.[15] Approximately 20 to 40 deaths occur from rotavirus infection each year in the United States, and globally the annual mortality from this infection is estimated at 600,000 to 850,000. Almost all children have had rotavirus disease by the time they are 3 years old. Natural immunity is protective against moderate and severe disease and is serotype-specific. The first rotavirus vaccine, which was licensed in July 1998 in the United States, was withdrawn in October 1999 because of an increased incidence of intussusception. This complication typically occurred 3 to 7 days after the first dose of vaccine.[15] Other rotavirus vaccines are now in clinical trials. One, developed by Merck, has a bovine rotavirus strain (Wistar calf 3) and is a human-bovine reassortant pentavalent oral vaccine containing strains G1, G2, G3, G4, and P1. Five clinical studies have been conducted in 2450 children younger than 1 year. In studies done to date, vaccine efficacy has been 70% for prevention of all rotavirus disease and approximately 99% for prevention of severe rotavirus disease. The incidences of fever and irritability are the same in vaccine recipients and placebo recipients. A large multicenter phase III study for safety, immunogenicity, and efficacy is currently under way in the United States and Finland. GlaxoSmithKline also has a rotavirus vaccine program. Trials are in progress for the vaccine based on the "89-12" human G1/P1 strain.[1,12] Pertussis in Adolescents and Adults Despite effective acellular pertussis vaccines for infants, the incidence of pertussis has continued to increase. The number of adults serving as vectors for infecting infants too young to be immunized has increased.[16,17] The APERT (Acellular Pertussis) trial examined the incidence of pertussis in adults, assessed the safety and efficacy of acellular pertussis vaccine in adults, and determined the immune response to pertussis. Study subjects between 15 and 65 years of age were randomized to receive either GlaxoSmithKline's acellular pertussis vaccine (without diphtheria and tetanus toxoids) or hepatitis A vaccine. There was no difference in the occurrence of fever associated with either vaccine, and the rate of cough did not vary between vaccine groups, but lumps at the injection site and swelling were more frequently seen in female than male recipients of acellular pertussis vaccine. Similar trends were seen for redness and soreness. The point estimate of vaccine efficacy varied by case definition. For a stringent case definition including serologic criteria, however, it was 77%. Other analyses, including cost data, have not yet been completed. Additional candidate vaccines are in trials.[8,12,18] It is hoped as well that an adult diphtheria, tetanus, and acellular pertussis preparation will be available soon. Human Papillomavirus Infection There are 120 types of human papillomavirus (HPV) identified. HPV causes essentially all cervical cancer and anogenital warts. HPV is a DNA tumor virus similar to SV40 and polyomavirus. Natural immunity following infection results in clearance of the infection in most cases. Unfortunately, when the immune system fails to control the infection, the progression toward cellular atypia, carcinoma in situ, and cancer begins. Types 16, 18, 31, 33, 35, 45, 51, 52, and 56 have been associated with cervical and other lower genital tract cancers. Types 16, 18, 31, and 45 account for 80% of cervical cancer and are the types being targeted in current phase I and II trials of vaccines. These trials have demonstrated safety and immunogenicity, but phase III trials are necessary to demonstrate that the vaccine against type 16 can prevent infection. Several vaccination strategies are being explored. The most advanced programs make use of virus-like particles consisting of the outer coat protein of the virus (produced in either insect cells or yeast) and E7 protein coupled to various things. These vaccines are in either phase I or II trials.[19,20] The NIH is examining the role of vaccine therapy in treating patients with recurrent or persistent cervical cancer. Genital Herpes Herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) cause a variety of illnesses involving the skin (commonly orofacial and genital herpes) and the CNS (herpes encephalitis), as well as neonatal herpes and disseminated herpes. Despite effective antiviral therapy, HSV infections remain a significant public health problem. Vaccines may offer the best hope for controlling the spread of infection and limiting disease. Three types of prophylactic vaccines are in clinical trials. These are based on adjuvant subunits on HSV-1 or HSV-2 comprising protein (gB or gD), a replication-incompetent viral mutant, and a DNA vaccine. Other strategies include genetically altered mutants and vectors. Most of these are in preclinical trials.[21] Results of phase I and II trials of subunit vaccines were promising, but the efficacy study demonstrated that infection occurred despite high antibody levels.[22] If a prophylactic vaccine is shown to be effective in controlling genital herpes, it may be important to then consider prevention of other HSV disease. Tuberculosis Given the problem of increasing antituberculous-drug resistance globally and the fact that tuberculosis is one of the leading causes of death around the world, an improved vaccine against tuberculosis is urgently needed.[23] In many countries other than the United States, BCG vaccine is used for tuberculosis prevention. This vaccine is effective in preventing miliary tuberculosis and tuberculous meningitis, but not in preventing pulmonary tuberculosis. Pulmonary tuberculosis is the most contagious form of the disease, however, so BCG is recommended only selectively in the United States. BCG in this country is indicated for infants and children who: Are purified protein derivative- negative and are continually and intimately exposed to contagious adults or to adults who have multidrug-resistant tuberculosis (especially with resistance to isoniazid and rifampin). Cannot take long-term prophylactic medication. Cannot be separated from the contagious adult. Research on vaccines continues to represent a key approach to understanding and controlling tuberculosis.[12,23] There are 9 tuberculosis vaccine projects in early preclinical development. They involve various mechanisms, including an rDNA technology to express and deliver protective antigens of Mycobacterium tuberculosis using other recombinant vaccine vectors (such as poxvirus or Salmonella species). Other tuberculosis vaccines under investigation involve genetically attenuated M tuberculosis strains, killed organism preparations, vaccines based on atypical mycobacteria, and DNA subunit vaccines that do not compromise the tuberculin skin test. Malaria This serious, sometimes fatal disease caused by Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae occurs in more than 100 countries and territories. Some 40% of the world's population is at risk. The World Health Organization estimates that 300 million to 500 million cases of malaria occur annually and more than 1 million people die of malaria every year.[24] Approximately 1200 cases of malaria are diagnosed in the United States each year. The majority of cases in the United States occur in immigrants and travelers from areas where malaria is endemic, especially sub-Saharan Africa and the Indian subcontinent. A vaccine using a peptide-based conjugate and fusion protein is in clinical trials.[1,12,25] Most other malaria vaccines are not yet in clinical trials. Meningococcal Disease Each year, meningococcal disease is diagnosed in 2400 to 3000 persons in the United States, resulting in an incidence rate of 0.8 to 1.3 per 100,000 population.[26] The case-fatality rate for meningococcal disease is 10%, despite the continued sensitivity of meningococci to many antibiotics, including penicillin. More than half of cases among infants younger than 1 year are caused by serogroup B meningococci, for which no vaccine is licensed or available in the United States (the quadrivalent A/C/Y/W-135 vaccine is the formulation currently available). Serogroup A/C/Y/W-135 meningococcal polysaccharides have been chemically conjugated to protein carriers. These meningococcal conjugate vaccines provoke a T-cell-dependent response that induces a stronger immune response in infants, primes immunologic memory, and leads to a booster response to subsequent doses. These vaccines are expected to provide a longer duration of immunity than polysaccharides, even when administered in an infant series, and may provide herd immunity through protection from nasopharyngeal carriage. Because the group B polysaccharide is not immunogenic in humans, immunization strategies directed at serogroup B have focused primarily on noncapsular antigens. Several of these vaccines, developed from specific strains of serogroup B meningococci, have been safe, immunogenic, and efficacious among children and adults and have been used to control outbreaks in South America and Scandinavia. Strain-specific differences in outer membrane proteins suggest that these vaccines may not provide protection against all serogroup B meningococci, however. No serogroup B vaccine is currently licensed or available in the United States. Herpes Zoster The use of a varicella-zoster vaccine to prevent herpes zoster is under investigation. The information gathered thus far suggests that varicella vaccine indeed reduces the incidence of zoster. An 80% reduction of zoster incidence was reported in patients with leukemia who had been immunized with a varicella vaccine compared with patients with leukemia who had natural varicella.[27 ]All of the zoster seen in vaccinated individuals was mild and without complications. The vaccine has been used in persons older than 40 years to ascertain whether zoster can be prevented by boosting cell-mediated immune responses.[1,27] The initial findings are also promising for prevention of postherpetic neuralgia. Multidrug-Resistant Staphylococcal Infection Staphylococci, which are considered to be opportunistic pathogens, normally colonize the human anterior nares, skin, and GI tract but rarely cause systemic infections in otherwise healthy individuals. In 1999, 20 million hospitalized patients in the United States received nearly 44 million courses of anti-infective drugs; of the 20 million, 6.4% (1.27 million) had cultures positive for Staphylococcus aureus. In this population, S aureus infections were associated with a 25% crude mortality. Total direct costs for S aureus-associated infections in 2000 were estimated to be $435.5 million ($32,100 per patient).[8] Nabi StaphVAX is a polysaccharide conjugate vaccine derived from S aureus capsular polysaccharides covalently bonded to a carrier protein to induce polyclonal antibodies directed at multiple sites on the bacterial surface polysaccharide coat. The vaccine targets serotypes 5 and 8, which are responsible for 85% to 90% of S aureus infections. Phase I and II studies have demonstrated safety and immunogenicity. Immune response has persisted for several years, and an optimal dose for healthy volunteers and for patients with end-stage renal disease has been established. A pivotal phase III clinical trial showed the vaccine to be safe and 57% effective in reducing the incidence of life-threatening S aureus bacteremias for 10 months following vaccination.[28] There are 6 other staphylococcal vaccine projects under way based on polysaccharides, chimeric viruses, and conjugated epitopes on carriers. Respiratory Viral Infections FluMist, a live, cold-adapted flu vaccine for nasal administration, has been given to more than 10,000 persons, including 6500 children between 1 and 18 years of age.[29] No serious adverse effects were reported. In previous studies, influenza vaccines similar to FluMist and containing 1, 2, or 3 viruses have been well tolerated in more than 8000 children and adults.[29] It is possible that FluMist could receive approval before the end of 2001. Major questions surrounding its use are whether healthy young children should receive it routinely and how it should be used. Other influenza vaccine programs include research on a variety of live attenuated virus vaccines, killed virus vaccines, recombinant hemagglutinin subunit vaccines, and new adjuvants for old vaccines.[1,12] Other Respiratory Vaccines There are 6 programs devoted to development of respiratory syncytial virus vaccines, including live viruses, recombinant proteins, and DNA methods. There are 3 programs devoted to parainfluenza virus vaccine development, and 1 parainfluenza virus vaccine is in clinical trials.[1,12] Future Trends The use of immunization registries can improve measurement of vaccine coverage. Current methods of assessing immunization coverage rates, such as the National Immunization Interview Survey or office record assessment by immunization programs or managed care organizations, are labor-intensive, and each employs a different methodology. Registries can identify pockets of underimmunization, thereby improving public health outreach, and will be essential for optimal management of immunization programs as more vaccines become available.[12,30] The concept of prevention for life -- pediatric vaccines that protect through adolescence and adulthood -- is emerging as viable. Improved delivery of vaccines through advances in inoculation techniques, such as needleless injections, transdermal techniques, mucosal administration (such as intranasal influenza vaccine), and oral delivery (using microencapsulation or food products), will be an important area of development. In addition, application of vaccine technology to the development of immunotherapy for allergies, cancer, and autoimmune diseases is on the horizon. Table 1. Decline in vaccine-preventable diseases in the United States Disease Maximum annualincidence Year of maximumincidence Incidence in 2000 Change (%) Diphtheria 206,939 1921 1 -100.00 Measles 894,134 1941 81 -99.97 Mumps 152,209 1968 391 -98.89 Pertussis 265,269 1934 7298 -97.52 Poliomyelitis (paralytic) 21,269 1952 0 -99.99 Rubella 57,686 1969 271 -99.67 Congenital rubella syndrome 20,000 1964 - 1965 5 -99.98 Tetanus 1560 1923 33 -96.92 Hepatitis B 300,000 NA 7694 NA Varicella 3,500,000 1994 NA -87%* NA, not available. *Percentage for Philadelphia only. Table 2. Opportunities for improving effectiveness and utilization rates of existing vaccines Vaccine Burden of preventable disease Hepatitis A vaccine 17,047 cases in 1999 Hepatitis B vaccine 7964 cases reported to CDC in 1999 Meningococcal A/C/Y/W-135 vaccine Annual burden, 2400 - 3000 cases; case-fatality rate of 10% Pneumococcal polysaccharide 23-valent vaccine Annual burden, 150,000 - 570,000 cases of pneumonia; 16,000 - 55,000 cases of bacteremia; 3000 - 6000 cases of meningitis Varicella vaccine 3.5 million cases annually before 1995, with an 87% decrease since then in areas where vaccine coverage is more than 70% Table 3. Necessary vaccines in clinical or preclinical trials Adenovirus Campylobacter jejuni Cytomegalovirus Encephalitis, eastern equine Encephalitis, Japanese Encephalitis, tick-borne Encephalitis, Venezuelan equine Encephalitis, western equine Enterohemorrhagic Escherichia coli E coli urinary tract infections Epstein-Barr virus Extended serotype conjugate pneumococcal vaccines Groups A and B streptococci Haemophilus ducreyi (chancroid) Hepatitis C Herpes simplex virus types 1 and 2 HIV Human papillomavirus Influenza Malaria Meningococci (conjugates and combination vaccines) Mycobacteria (Mycobacterium tuberculosis, Mycobacterium leprae) Neisseria gonorrhoeae Non-typeable Haemophilus influenzae and Moraxella species Parainfluenza Pertussis (adult) Respiratory syncytial virus Rotavirus Salmonella Shigella References Plotkin SA. Vaccines in the 21st century. Infect Dis Clin North Am. 2001;15:307-324. Marshall GS. Cytomegalovirus vaccines -- two decades of progress. Herpes. 1997;4:20-24. Frey SE, Harrison C, Pass RF, et al. Effects of antigen dose and immunization regimens on antibody responses to a cytomegalovirus glycoprotein B subunit vaccine. J Infect Dis. 1999; 180:1700-1703. Adler SP, Plotkin SA, Gonczol E, et al. A canarypox vector expressing cytomegalovirus (CMV) glycoprotein B primes for antibody responses to a live attenuated CMV vaccine (Towne). J Infect Dis. 1999;180:843-846. Halsey N, Klein D. Report of a workshop: immunization of pregnant women. Pediatr Infect Disease J. 1990;9:714-716. Pichichero M. New combination vaccines. Pediatr Clin North Am. 2000;47:407-426. Baker CJ, Rench MA, Edwards MS, et al. Immunization of pregnant women with a polysaccharide vaccine of group B streptococcus. N Engl J Med. 1988;319:1180-1185. Centers for Disease Control and Prevention Advisory Committee on Immunization Practices. February 21-22, 2001; Atlanta. Available at:www.cdc.gov/nip/acip. Dolin R. HIV vaccines for prevention of infection and disease in humans. Infect Dis Clin North Am. 2000;14:1001-1016. VaxGen Web Site. Available athttp://www. vaxgen.com. Accessed June 22, 2001. Robinson HL, Montefiori DC, Johnson RP, et al. Neutralizing antibody-independent containment of immunodeficiency virus challenges by DNA priming and recombinant pox virus booster immunizations. Nat Med. 1999;5:526-534. The Jordon Report. Available at:www.niaid.nih.gov. Accessed April 16, 2001. Clements-Mann ML, Weinhold K, Matthews TJ, et al. Immune responses to human immunodeficiency virus (HIV) type 1 induced by canarypox expressing HIV-1MN gp120, HIV-1SF2 recombinant gp120, or both vaccines in seronegative adults. NIAID AIDS Vaccine Evaluation Group. J Infect Dis. 1998;177:1230-1246. Centers for Disease Control and Prevention. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR. 1998;47(RR19). Murphy TV, Gargiullo PM, Massoudi MS, et al. Intussusception among infants given an oral rotavirus vaccine. N Engl J Med. 2001;344:564-572. Decker MD, Edwards KM, Steinhoff MC, et al. Comparison of 13 acellular pertussis vaccines: adverse reactions. Pediatrics. 1995;96(3 pt 2):557-566. Guris D, Strebel PM, Bardenheier B, et al. Changing epidemiology of pertussis in the United States: increasing reported incidence in adolescents and adults, 1990-96. Clin Infect Dis. 1999;28:1230-1237. Orenstein WA, Hadler S, Wharton M. Trends in vaccine-preventable diseases. Semin Pediatr Infect Dis. 1997;8:23-33. Bosch FX, Manos MM, Munoz N, et al. Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International Biological Study on Cervical Cancer (IBSCC) Study Group. J Natl Cancer Inst. 1995;87:796-802. ARHP Clinical Proceedings HPV and Cervical Cancer. Washington, DC: Association of Reproductive Health Professionals; March 2001:1-31HVC. Available at:http://www.arhp.org. Stanberry LR, Cunningham AL, Mindel A, et al. Prospects for control of herpes simplex virus disease through immunization. Clin Infect Dis. 2000;30:549-566. Corey L, Langenberg AG, Ashley R, et al. Recombinant glycoprotein vaccine for the prevention of genital HSV-2 infection: two randomized controlled trials. Chiron HSV Vaccine Study Group. JAMA. 1999;282:331-340. Bloom B. BCG's implications for future vaccines against tuberculosis. In: Tuberculosis, Pathogenesis, Protection and Control. Washington, DC: American Society for Microbiology; 1994:517-557. World Health Organization. Available at: www. who.int/inf-fs/en/fact094.html. Plotkin SA, Orenstein WA, eds. Vaccines. 3rd ed. Philadelphia: WB Saunders Co; 1994. Centers for Disease Control and Prevention. Prevention and control of meningococcal disease: recommendations of the Advisory Committee of Immunization Practices. MMWR. 2000;49 (RR07):1-10. Watson B, Rothstein E. Varicella vaccine: progress 4 years after licensure. Pediatr Ann. 1999; 28:516-529. Fattom A, Li X, Cho YH, et al. Effect of conjugation methodology, carrier protein, and adjuvants on the immune response to Staphylococcus aureus capsular polysaccharides. Vaccine. 1995;13:1288-1293. Belshe RB, Mendelman PM, Treanor J, et al. The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenzavirus vaccine in children. N Engl J Med. 1998;338:1405-1412. Borenstein P, Levenson R, Watson B, Lutz J. Potential use of immunization registries for provider education. Am J Preventive Med. 1997; 13(suppl):97-102. *sorry, unable to upload the frame with table and it can only be shown in words format.