Capitol 18 Vaccines

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common usage.Experience has shown that not every vaccinecandidate that was successful in laboratory and animal stud-ies prevents disease in humans.Some potential vaccinescause unacceptable side effects,and some may even worsenthe disease they were meant to prevent.Live virus vaccinespose a special threat to those with primary or acquired im-munodeficiency (see Chapter 19).Stringent testing is an ab-solute necessity,because vaccines will be given to largenumbers ofwell persons.Adverse side effects,even those thatoccur at very low frequency,must be balanced against the po-tential benefit ofprotection by the vaccine.Vaccine development begins with basic research.Recentadvances in immunology and molecular biology have led toeffective new vaccines and to promising strategies for findingnew vaccine candidates.Knowledge ofthe differences in epi-topes recognized by T cells and B cells has enabled immunol-ogists to begin to design vaccine candidates to maximizeactivation ofboth arms ofthe immune system.As differencesin antigen-processing pathways became evident,scientistsbegan to design vaccines and to use adjuvants that maximizeantigen presentation with class I or class II MHC molecules.

chapter

Active and Passive Immunization

Designing Vaccines for Active Immunization

Whole-Organism Vaccines

Purified Macromolecules as Vaccines

Recombinant-Vector Vaccines

DNA Vaccines

Multivalent Subunit Vaccines

Vaccines

       

the early vaccination trials ofEdward Jenner andLouis Pasteur.Since those pioneering efforts,vac-cines have been developed for many diseases that were oncemajor afflictions ofmankind.The incidence ofdiseases suchas diphtheria,measles,mumps,pertussis (whooping cough),rubella (German measles),poliomyelitis,and tetanus has de-clined dramatically as vaccination has become more com-mon.Clearly,vaccination is a cost-effective weapon fordisease prevention.Perhaps in no other case have the bene-fits ofvaccination been as dramatically evident as in theeradication ofsmallpox,one ofmankind’s long-standingand most terrible scourges.Since October 1977,not a singlenaturally acquired smallpox case has been reported any-where in the world.Equally encouraging is the predictederadication ofpolio.The last recorded case ofnaturally ac-quired polio in the Western Hemisphere occurred in Peru in1991,and the World Health Organization (WHO) predictsthat paralytic polio will be eradicated throughout the worldwithin the next few years.A new addition to the weaponsagainst childhood disease is a vaccine against bacterial pneu-monia,a major cause ofinfant death.A crying need remains for vaccines against other diseases.Every year,millions throughout the world die from malaria,tuberculosis,and AIDS,diseases for which there are no effec-tive vaccines.It is estimated by the World Health Organiza-tion that 16,000 individuals a day,or 5.8 million a year,become infected with HIV-1,the virus that causes AIDS.Aneffective vaccine could have an immense impact on the con-trol ofthis tragic spread ofdeath and disaster.In addition tothe challenges presented by diseases for which no vaccines ex-ist,there remains the need to improve the safety and efficacyofpresent vaccines and to find ways to lower their cost anddeliver them efficiently to all who need them,especially in de-veloping countries ofthe world.The WHO estimates thatmillions ofinfant deaths in the world are due to diseases thatcould be prevented by existing vaccines (see Clinical Focus).The road to successful development ofa vaccine that canbe approved for human use,manufactured at reasonablecost,and efficiently delivered to at-risk populations is costly,long,and tedious.Procedures for manufacture ofmaterialsthat can be tested in humans and the ways they are tested inclinical trials are regulated closely.Even those candidate vac-cines that survive initial scrutiny and are approved for use inhuman trials are not guaranteed to find their way into

Vaccination with DNA

414

PART IV

The Immune System in Health and Disease

recently of a causal relationship betweenvaccination and autism, a condition ofunknown etiology. Most such reportsare based solely on the coincidental tim-ing of vaccination and onset of disease,or on limited sampling and poor statisti-cal analyses. So far, no alleged asso-ciations have withstood scrutiny thatincluded large population samples andacceptable statistical methods.While children in this country are pro-tected against a variety of once-deadlydiseases, this protection depends oncontinuation of our immunization pro-grams. Dependency on herd immunity isdangerous for both the individual andsociety. Adverse reactions to vaccinesmust be examined thoroughly, of course,and if a vaccine causes unacceptableside reactions, the vaccination programmust be reconsidered. At the same time,anecdotal reports of disease brought onby vaccines, and unsupported beliefs,such as the contention that vaccinesweaken the immune system, must becountered by correct information fromtrusted sources. To retreat from ourprogress in immunization by noncom-pliance will return us to the age whenmeasles, mumps, whooping cough, andpolio were part of the risk of growing up.Children in the developing world suf-fer from a problem different from thosein the United States. Examination of in-fant deaths worldwide shows that exist-ing vaccines could save the lives ofmillions of children. As seen in the table,there are safe, effective vaccines for fiveof the top ten killers of children. Al-though the list of diseases in the table in-cludes HIV, TB, and malaria, for whichno vaccines are available, administrationof the vaccines that are recommendedfor infants in the United States could cutchild mortality in the world by approxi-mately half.What barriers exist to the achievementof worldwide vaccination and completeeradication of many childhood diseases?The inability to achieve higher levels of

Many

previously commonchildhood diseases are seldom seen inthe United States, a testament to the ef-fectiveness of vaccination. A major bar-rier to similar success in the rest of theworld is the difficulty of delivering vac-cines to all children. However, even athome the U.S. is becoming a victim ofits own success. Some parents whohave never encountered diseases nownearly vanquished in the U.S. do notconsider it important to have their in-fants vaccinated or they may be lax inadhering to recommended schedules ofimmunization. Others hold the unin-formed belief that the risks associatedwith vaccination outweigh the risk of in-fection. This flawed reasoning is fueledby periodic allegations of linkage be-tween vaccination and various disor-ders, such as the report circulating

CLINICAL FOCUS

Vaccination: Challenges in theU.S. and Developing Countries

Genetic engineering techniques can be used to develop vac-cines to maximize the immune response to selected epitopesand to simplify delivery ofthe vaccines.This chapter de-scribes the vaccines now in use and describes vaccine strate-gies,including experimental designs that may lead to thevaccines ofthe future.

Active and Passive Immunization

Immunity to infectious microorganisms can be achieved byactive or passive

immunization

.In each case,immunity canbe acquired either by natural processes (usually by transferfrom mother to fetus or by previous infection by the organ-ism) or by artificial means such as injection ofantibodies orvaccines (Table 18-1,on page 416).The agents used for in-ducing passive immunity include antibodies from humans oranimals,whereas active immunization is achieved by inocu-lation with microbial pathogens that induce immunity butdo not cause disease or with antigenic components from thepathogens.This section describes current usage ofpassiveand active immunization techniques.

Passive Immunization Involves Transferof Preformed Antibodies

Jenner and Pasteur are recognized as the pioneers ofvaccina-tion,or induction ofactive immunity,but similar recogni-tion is due to Emil von Behring and Hidesaburo Kitasato fortheir contributions to passive immunity.These investigatorswere the first to show that immunity elicited in one animalcan be transferred to another by injecting it with serum fromthe first (see Clinical Focus,Chapter 4).Passive immunization,in which preformed antibodies aretransferred to a recipient,occurs naturally by transfer ofma-ternal antibodies across the placenta to the developing fetus.Maternal antibodies to diphtheria,tetanus,streptococci,rubeola,rubella,mumps,and poliovirus all afford pas-sively acquired protection to the developing fetus.Maternal

antibodies present in colostrum and milk also provide pas-sive immunity to the infant.Passive immunization can also be achieved by injecting arecipient with preformed antibodies.In the past,before vac-cines and antibiotics became available,passive immunizationprovided a major defense against various infectious diseases.Despite the risks (see Chapter 16) incurred by injecting ani-mal sera,usually horse serum,this was the only effective ther-apy for otherwise fatal diseases.Currently,there are severalconditions that warrant the use ofpassive immunization.These include:

Deficiency in synthesis ofantibody as a result of congenital or acquired B-cell defects,alone or togetherwith other immunodeficiencies.

Exposure or likely exposure to a disease that will causecomplications (e.g.,a child with leukemia exposed tovaricella or measles),or when time does not permitadequate protection by active immunization.

Vaccines

CHAPTER

415

Infection by pathogens whose effects may be amelioratedby antibody.For example,ifindividuals who have notreceived up-to-date active immunization against tetanussuffer a puncture wound,they are given an injection of horse antiserum to tetanus toxin.The preformed horseantibody neutralizes any tetanus toxin produced by

Clostridium tetani

in the wound.Passive immunization is routinely administered to indi-viduals exposed to botulism,tetanus,diphtheria,hepatitis,measles,and rabies (Table 18-2).Passively administered anti-serum is also used to provide protection from poisonoussnake and insect bites.Passive immunization can provide im-mediate protection to travelers or health-care workers whowill soon be exposed to an infectious organism and lack ac-tive immunity to it.Because passive immunization does notactivate the immune system,it generates no memory re-sponse and the protection provided is transient.For certain diseases such as the acute respiratory failure inchildren caused by respiratory syncytial virus (RSV),passive

Estimated annual deaths worldwide of children under

years ofage, by pathogen

PathogenDeaths (millions)

Pneumococcus

1.2

Measles

1.1

Hemophilus (a–f, nst)

0.9

Rotavirus

0.8

Malaria

0.7

HIV

0.5

RSV

0.5

Pertussis

0.4

Tetanus

0.4

Tuberculosis

0.1

Pathogens shown in bold are those for which an effective vaccine exists.

A licensed vaccine is being tested for possible side-effects.SOURCE: Adapted from Shann and Steinhoff,

1999

Lancet

354

(Suppl II):

7–11

vaccination even in the United States is anindication of the difficulty of the task. Evenif we assume that suitable vaccines havebeen developed and that compliance isuniversal, the ability to produce and deliverthe vaccines everywhere is a profoundchallenge. The World Health Organization(WHO) has stated that the ideal vaccinewould have the following properties:

Affordable worldwide

Heat stable

Effective after a single dose

Applicable to a number of diseases

Administered by a mucosal route

Suitable for administration early in lifeFew, if any, vaccines in common use to-day conform to all of these properties.However, the WHO goals can guide us inthe pursuit of vaccines useful for world-wide application. They further aid us insetting priorities, especially for develop-ment of the vaccines needed most in de-veloping countries. For example, anHIV/AIDS vaccine that meets the WHOcriteria could have an immediate effecton the world AIDS epidemic, whereasone that does not will require further de-velopment before it reaches the popula-tions most at risk.Immunization saves millions of lives,and viable vaccines are increasingly avail-able. The challenge to the biomedical re-search community is to develop better,safer, cheaper, easier-to-administer formsof these vaccines so that worldwide im-munization becomes a reality.

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