Vaccines in the Pipeline -- An Overview

[Guest guest]

From

The usual garbage - and the decline in disease is NOT what is signficant -

it is the decline in death from the disease and it had already declined

pre-vax.

Sheri

Vaccines in the Pipeline -- An Overview

http://id.medscape.com/45751.rhtml?srcmp=id-120701

Barbara , 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.

GlaxoKline 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 GlaxoKline'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 Year of Incidence Change

annualincidence maximumincidence in 2000 (%)

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 21,269 1952 0 -99.99

(paralytic)

Rubella 57,686 1969 271 -99.67

Congenital 20,000 1964 - 1965 5 -99.98

rubella

syndrome

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 Annual burden, 2400 - 3000 cases;

vaccine case-fatality rate of 10%

Pneumococcal polysaccharide Annual burden, 150,000 - 570,000 cases of

23-valent vaccine 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

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