Vaccines in the Pipeline -- An Overview

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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 serotyp