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Chapter 9
Antibiotics ant' Vaccines
The production of antibiotics and vaccines is a further type of microbial
processing that may be of great importance to developing countries.
Antibiotics are antimicrobial substances produced by living microorgan-
isms; many are used therapeutically and at times prophylactically in the
control of infectious diseases. They act by inhibiting the growth of the infect-
ing organisms. Some are effective against a wide range of infectious agents
and are known as "broad spectrum," whereas others are more specific. Un-
fortunately, for many infecting and disease-producing microorganisms (patho-
gens) there are as yet no effective antibiotics.
Vaccines, in contrast, are preparations of either dead organisms (or specific
fractions thereof) or living attenuated microorganisms that may be admin-
istered to man or animals to stimulate their immunity to infection by the
same or closely related organisms. The effectiveness of vaccines in controlling
disease can vary widely. For example, smallpox vaccine, commonly prepared
from the vaccinia lesions on the skin of inoculated calves or sheep or from the
allantoic membranes of inoculated chick embryos, produces a high degree of
immunity in vaccinated individuals and has been highly effective in con-
trolling the disease. Measles vaccine, also prepared from an attenuated live
virus, is likewise highly effective and produces a degree of immunity that is
demonstrable by measurement of antibody titers, usually for a period of
8-10 years or more. These two vaccines produce immunity by infection with
live virus and thus are long-acting. Influenza, on the other hand, may be
prevented by the parenteral injection of vaccines of influenza viruses that
have been grown in chick embryos and rendered noninfectious by formalin or
ultraviolet irradiation. With such a dead vaccine, the duration of immunity
rarely exceeds one year, and, since the causative agent (virus) of influenza is
capable of mutating frequently, different vaccines usually must be prepared
to combat each mutant strain.
. . . .
A _ A: 1~: _ `: ~ _ _ ~ :1 ~ _ 1 ~ t 1
I; `~u vaccines are oom use a in modern medicine lo counter
infectious diseases. Vaccines are used as prophylactic agents to increase im-
munity and to prevent subsequent infection with more virulent strains; anti-
biotics are employed most often as therapeutic agents to control disease after
its onset, although they may also be used prophylactically against some
158
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ANTIBIOTICS AND VACCINES
159
organisms. There are, in addition, other antimicrobial drugs (not derived from
growing microorganisms) which m`ay be used for control of infection. These
are generally used therapeutically, although at times, as with malaria, they
may be used to prevent infection.
In developing countries, the capacity to produce many of these disease-
fighting agents may only be realized further in the future than most other
processes described in earlier chapters of this report. Local manufacture of
drugs or vaccines requires considerable capital, a high degree of technology,
and specially trained personnel; the use of these assets to produce antibiotics
or vaccines locally must be viewed critically in relation to other needs for the
same limited resources.
Economies of scale usually make it possible for industrialized countries to
produce drugs more cheaply for large markets. Yet, in these industrialized
countries, the major portion of research on drugs and vaccines is likely to
relate directly to those diseases occurring within these industrialized areas,
that is, not to those in the developing countries where the need is greatest.
Many diseases of developing countries, including the major tropical dis-
eases, have attracted little attention and it may be that these diseases can best
be attacked by a concerted research effort in the countries where they are
endemic. Moreover, in view of the limited resources in these countries, shar-
ing of effort on a regional basis may be desirable at times; but even so, the
investment of time and money for this purpose in no way would be justifiable
until other necessary elements of the public health system were adequate.
These elements include:
· Public health statistics. Without good information on the principal
causes of illness and death, health planning is ineffective and development of
a health policy is impossible. A means of disseminating public health informa-
tion is a prerequisite for public health programs.
· Public health programs. The source and mode of transmission of the
target disease must be known. Effective programs may require control of
nonhuman hosts or their environments. For example, in conjunction with
drug administration, molluscicides may be required against snails for control
of schistosomiasis, milk pasteurization for control of typhoid fever, or the
destruction of mosquito-breeding areas for control of malaria.
· A health delivery system. An effective delivery system is a prerequisite
to achieving health policy objectives. An effective disease-control program
cannot be mounted without adequate storage facilities (generally low-temper-
ature) and adequate means for drug distribution and administration.
· Knowledge of the nutritional status of the population and its relation-
ship to disease. The interactions between an individual's nutritional state and
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160
MICROBIAL PROCESSES
infection must be taken into account in designing an effective disease-control
program.
This information on the health system will determine the kinds of vaccines
or antibiotics required and whether their local manufacture might be econom-
ically feasible.
In this regard, modern drug development programs use increasingly sophis-
ticated and sensitive analytical, chemical, and biochemical techniques. Drug
intermediates are frequently extracted from plants or microorganisms and
modified chemically to produce active substances. The distinction between
microbiologically derived antibiotics and other antimicrobial drugs becomes
less important as the criteria of efficacy and economics of production
methods determine the extent to which microbes should be employed to
synthesize a particular drug.
The World Health Organization (WHOJ provides assistance through the
establishment of integrated disease-control programs in most countries. The
objectives of this program include assistance in:
drugs.
· Developing a consistent approach to health policies;
Assuring safety and efficacy of drugs;
Achieving optimum utilization of drugs;
Providing supplies of drugs;
Exchange of data on drug experience among countries;
· Training of scientific personnel in the health field; and
· International collaboration in research and development on improved
Antibiotics and vaccines can be powerful tools for enhancing the health
and well-being of afflicted populations. The virtual eradication of smallpox
throughout the world is a fine example of the success of a coordinated disease-
control program. With greater use of microbial processes and with worldwide
collaboration other successes will follow.
Antibiotics
Probably no group of substances has been more thoroughly exploited than
the antibiotics. Yet no antibiotics exist today for effective treatment of many
of the diseases most prevalent in developing countries.
This is partly because of greater attention and resources being given to the
diseases of industrialized countries; it is also because of the inherent nature of
the diseases and their effects on human hosts. To be effective against a
disease-producing organism the antibiotic must be able to inhibit its growth
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ANTIBIOTICS AND VACCINES
161
or its production of toxic substances without having a similar effect on sur-
rounding host cells. This may be especially difficult when the organism is
localized in a particular tissue (as in the case of tuberculosis or leprosy) where
it is necessary to maintain a high concentration of the antibiotic over suffi-
cient time without adverse effects on the human or animal host.
Further, there is often a need to grow the disease-producing orgarusms out-
side the human or animal body, so that experimentation with potential con-
trol agents will be possible. With some organisms, this has not yet been
achieved. This inability to culture certain infecting organisms in vitro remains
a major obstacle to their control.
Many antibiotic-producing microorganisms have been isolated from soil by
a simple procedure: a soil sample containing millions of microorganisms is
suspended in water, the suspension is diluted severalfold, and samples are
transferred to Petri plates containing agar media of various nutritive composi-
tions. The plates are incubated until growth of the microorganisms occurs in
the form of individual colonies. If any of these colonies has produced an
antibiotic, it probably will have diffused into the agar and it can be detected
by spraying the agar with a suspension of bacteria susceptible to the anti-
biotic. The susceptible organisms form a solid lawn (growth) except where the
antibiotic has diffused. Where the antibiotic exists, their growth will be arrest-
ed and a clear zone will surround the colony that has produced the antibiotic.
Figure 9.1 illustrates zone formation for several different antibiotics.
Studies then can be carried out to determine the types of organisms in-
hibited by the antibiotic. The antibiotic-producing culture is grown in increas-
ingly larger volumes (in Erlenmeyer flasks or fermentation vessels) after deter-
mining the conditions favoring maximum production of the desired active
material. The antibiotic material may then be isolated and tested for potency
alla for its ability to produce side reactions or toxicity in animals. Finally it
can be prepared in still larger quantities (Figure 9.2~. Although basically
FIGURE 9.1 The effectiveness of several antibiotics against a single microorganis
can be simultaneously determined. Discs containing a variety of agents are tested to en-
able selection (according to zone sizes) of those which might be used in vivo. (Photo-
graph courtesy of BBL Microbiology Systems, Division of Becton, Dickinson and Com-
pany)
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Representative terms from entire chapter:
microbial processes
162
l. Reparation of Motion 2. Agar plate
1:100 1:10000 1: 100008
,_ ~ ~ it, )C) . . ~
15 Nil special nutrient medium
'~_. ~ ~~' m'4 me my
Soil sample 100 ml
Interim dist. water
3. Spray apparatus
for the spraying of the test
organism on the agar plate
Tort ^~nor~icn~~
Inhibitory Tect organism
Compres.cc~l zone \ /
air \ ,/ Inoenium
(A ~ ~ in ~ncuba'Dr',~ Puriflcat.<,n:
Grown
agar plate
6. Suitability test for
submerged culture
~6
#
.
7 days at 24-27° in
the shaken culture
9.
MICROBIAL PROCESSES
9 ml Petri dish
5ttri~c dist. water
_ Incubator 6 days at 25.
4. Evaluation of the S. Streak test
sprayed plate
for the determination or the
antihacterist spectrum
'] Tee<
ANTIBIOTICS AND VACCINES
163
examples of narrow-spectrum antibiotics that act against only a few bacterial
species.
The major microbial sources of useful antibiotics are the actinomycetes
(Streptomyces, Nocardia, Micromonospora) and molds or fungi (Penicillium,
Cephalosporium).
Human Diseases
Table 9.1 lists major tropical diseases and indicates the availability of
vaccines and antibiotics for their treatment. Much research remains to be
done to arrest tropical diseases, particularly schistosomiasis, malaria, filariasis,
trypanosomiasis (including African sleeping sickness and Chagas disease),
onchocerciasis, and leishmaniasis, all common parasitic infections in the trop-
ical zone. They are widespread, chronic, and may affect every member of a
community. Although they are rare in industrialized countries in the temper-
ate zones, the number of people suffering from their effects in the developing
tropical regions runs into hundreds of millions. Their impact on individual
well-being and productivity, in addition to physical suffering, has a profound
effect on economic and social development.
Most therapeutically useful antibiotics exert their inhibitory effects only
on bacteria. Since many of the tropical diseases are caused by protozoa,
multicellular animal parasites, and viruses, other agents must be sought.
Methods must be developed for cultivation of the parasites under laboratory
conditions and for detection and assay of agents that can inhibit their growth.
Although the list of pathogens yet to be brought under control is lengthy,
specific drugs and antibiotics discussed below have been developed for a
number of widespread diseases.
Antifungal Agents Both superficial and systemic diseases result from in-
fection of the skin and viscera by pathogenic fungi.
Typical skin infections, like chromomycosis and mycetoma, are caused by
a diverse group of soil organisms. These infections develop slowly and are
usually chronic. Mycetoma has been treated with penicillin and chromo-
mycosis with amphotericin B. but surgical excision of small lesions is most
effective. Better drugs are needed.
Histoplasmosis is a lung disease caused by inhaling spores from soil-borne
fungi. The causative organism prefers soils contaminated by bat or bird drop-
pings; caves and chicken coops are notorious sources of the infection.
Amphotericin B has been used successfully in the treatment of histoplasmosis.
Blastomycosis is also a lung disease with secondary infections appearing on
the skin. Amphotericin B has been used in the treatment of this disease.
Tine a favosa is a fungal infection of the skin and scalp commonly seen in
children. Griseofulvin has been shown to produce good curative effects.
164
MICROBIAL PROCESSES
TABLE 9.1 Availability of Antibiotics, Chemicals, or Vaccines for Treatment or Preven-
tion of Various Tropical Diseases (x = reported successful use; ? = possible use or testing)
Diseases
Antibiotics Chemicals Vaccines
Protozoan Diseases
Amebiasis (Amebic dysentery) x Quinolines
Leishmaniasis (Kala-azar) ? Antimonials
Malaria ? Quinolines
Trypanosomiasis (Sleeping sickness) Amidines, Suramin
Fungal Diseases
Blastomycosis
Chromomycosis
Histoplasmosis (Darling's disease)
Mucormycosis
Mycetoma
Rhinosporidiosis
Sporotrichosis
Tinea favosa (Favus)
Tinea imbricata (Tokelau)
Bacterial Diseases
x
x
x
x Sulfas
x
x
x
Iodides
Brucellosis (Undulant fever) x
Cholera x x
Cutaneous Diphtheria x
Gonorrhea x
Leprosy ? Sulfones
Leptospirosis (Weil's disease) x ?
Relapsing Fever x Arsenicals
Shigellosis (Bacillary dysentery) x
Syphilis x
Tetanus x
Tuberculosis x Isoniazides x
Typhoid Fever
Yaws
Rickettsial Diseases
Boutonneuse Fever
Epidemic Typhus
Murine Typhus
Scrub Typhus
x
x
x
x
x
x
x
x
x
Mucormycosis is an infection of the intestines, lungs, and central nervous
system, or skin. It is caused by one of a class of opportunistic fungi that
generally do not infect the normal host but may cause disease in debilitated
patients. For example, mucormycosis of the lung is associated with leukemia
and mucormycosis of the intestines with malnutrition. In some instances,
amphotericin B has been effective.
Antibacterial Agents Many drugs are available for the treatment and con-
trol of tuberculosis, a disease of bacterial etiology that is still highly prevalent
ANTIBIOTICS AND VACCINES
TABLE 9.1 Continued
165
Diseases
Antibiotics Chemicals Vaccines
Viral Diseases
Bwamba Fever
Dengue
Infectious Hepatitis
Influenza A&B
Measles (Rubeola)
Poliomyelitis
Rabies
Rift Valley Fever
Smallpox (Variola)
Trachoma
West Nile Fever
Yellow Fever
Zika Fever
Helminth Diseases
Ancylostomiasis (Hookworm)
Ascariasis (Roundworm)
Clonorchiasis (Oriental liver fluke)
Dipetalonemiasis
Dipylidiasis
Dracunculiasis (Dragonworm)
Fascioliasis (Sheep liver fluke)
Filariasis (Elephantiasis)
Gastrodisciasis
Gnathostomiasis (Creeping eruption)
Hydatid disease
Hymenolepiasis (Dwarf tapeworm)
Loiasis (Eyeworm)
Onchocerciasis (River blindness)
Paragonimiasis (Oriental lung fluke)
Schistosomiasis (Bilharziasis)
Strongyloidiasis
Taeniasis (Tapeworm)
, ~ ... .
rlcnmosls
Trichostrongyliasis
Trichuriasis (Whipworm)
?
x
x
x
x
Sulfonamides
Benzimidazoles
Benzimidazoles
Phenolics
Pyrazines
Salicylamides
Pyrazines
Phenolics
Pyrazines
Benzimidazoles
Pyrazines
Salicylamides
Pyrazines
Pyrazirles
Phenolics
Nitroim~dazoles
Benzimidazoles
Salicylamides
Benzimidazoles
Benzimidazoles
Benzimidazoles
x
x
in developing countries. When properly used, isoniazid and rifampin in com-
bination with either streptomycin, p-aminosalicylic acid, or thiacetazone are
highly effective therapeutic agents. Effective control of tuberculosis has been
achieved, however, only in those countries where public health practices per-
mit early detection of the disease by tuberculin testing and chest X-radiog-
raphy, and by early treatment of all those who have had contact with those
who are infected. Continuing control has been successful only where long-
term drug administration can be assured.
Leprosy is a chronic infectious disease caused by Mycobacterium leprae.
General treatment includes enhancement of personal and environmental
hygiene and an ample, well-balanced diet. Although the sulfones (particularly
166
MICROBIAL PROCESSES
DDS, 4, 4' - diamino diphenyl sulfone) have been the most effective class of
drugs against leprosy, recent studies with the antibiotic rifampin at the WHO
laboratories in Caracas have shown promise.
The widespread use of antibiotics in the treatment of bacterial infection
has resulted in the emergence of numerous highly resistant pathogens. Drug
resistance has developed through selection and transfer of genetic information
(plasmids, extrachromosomal DNA) in microorganisms. Prevalence of drug-
resistant strains makes it imperative that new drugs be developed for treat-
ment of certain infectious diseases, particularly those caused by Haemophilus
influenzee, Neisseria gonorrhoeae, and pathogenic Enterobacteriaceae.
Other Antimicrobial Agents Of the rickettsial diseases, epidemic typhus
occurs in Africa and Europe. It is caused by Rickettsia prowozekii and can be
controlled with chloramphenicol. Boutonneuse fever, a disease of the spotted
fever group common in Africa, is caused by R. conorii. Chlortetracycline and
chloramphenicol have produced favorable results in patients with this disease.
The protozoa! disease amebiasis (amebic dysentery) is an infection by the
ameba Entamoeba his tolytica. Although amebiasis is not confined to the
tropics, its incidence is determined in part by the level of sanitation in a given
area. The majority of antibiotics showing activity against this ameba act in-
directly through their bacteriostatic activity rather than directly against this
parasite. However, two of them, oxytetracycline and fumagillin, appear to act
directly as amebacides and at times have been found effective in the treatment
of acute amebic dysentery.
Malaria may be the most serious widespread protozoa! disease. The organ-
isms, Plasmodium sp., are difficult to culture and are controlled only slowly
by the tetracyclines. The disease is currently controlled by chemicals (mair~ly
chloroquine derivatives) administered prophylactically and is treated chemo-
therapeutically by a variety of substances chemically related to quinine. WHO
has cautioned against widespread use of antibiotics for treatment of malaria
because of the risks of developing resistance in pathogenic bacteria, and
recommends antibiotics only in areas where chloroquine-resistant strains of
plasmodia are found.
Antitumor Agents The use of products of microorganisms has also been
extended to the area of cancer chemotherapy.
Antibiotics with antitumor properties are produced by some micro-
organisms and a few of these may be used therapeutically (i.e., adriamycin,
bleomycin, actinomycin D, mithramycin, mitomycin C).
The antitumor antibiotics are not a homogeneous group of compounds.
Their antibacterial and antitumor activities are not correlated, but some cor-
relation has been found between activities against transplantable tumors and
human tumors.
ANTIBIOTICS AND VACCINES
167
Antihelminths The only effective therapeutic agents as yet developed
against infestations ~ man and animals are chemical agents derived by other
than microbial processes (see Table 9.1~.
Animal Diseases
The most prevalent diseases of animals occurring in developing countries
are trypanosomiasis (sleeping sickness), Newcastle disease, rinderpest, African
swine fever, gastrointestinal parasitism, pasteurellosis, bovine pleuro-
pneumonia, heartwater, sheep pox, babesiosis, brucellosis, hog cholera, and
foot-and-mouth disease.
Trypanosomiasis occurs principally in Africa where the tsetse fly, by which
it is spread, is found in 700 million hectares of land and prevents the raising of
cattle. It is estimated that this vast area could support 125 million cattle and
an equal number of sheep and goats. There are no drugs or vaccines for this
parasitic disease, and development of effective ones is critically needed.
Gastrointestinal parasitism occurs worldwide in cattle, sheep, goats, swine,
and poultry. A number of parasites are involved, although the helminths
(roundworms) are the ones of prime importance. No vaccines are available,
but there are effective drugs for control of some of these parasites.
Pasteurellosis also occurs worldwide but is important primarily in Africa
and Asia. This bacterial disease affects cattle and buffalo and has a major
impact on draft animals. Vaccines and antibiotics are effective against the
disease, but delivery to the field in many countries presents difficulties.
Brucellosis occurs in naturally infected domestic animals in all parts of the
world. Brucellosis is a serious cause of abortion in cattle, and to a lesser degree
in sheep, goats, and swine. Vaccines and antibiotics are available for both
prevention and cure of this bacterial disease.
Hog cholera is a highly contagious viral disease. Although there are no
effective drugs, vaccines are available for control.
Foot-and-mouth disease is widespread in Europe, South America, the
Middle East, and Mexico. Although vaccines may be used for control of this
viral disease, they are type specific. To limit the spread of an outbreak, the
enzootic strains must be determined and specific vaccines prepared for use
against them. Control in many countries is through maintenance of quarantine
along with supervised vaccination.
Newcastle disease occurs worldwide and affects poultry, a major protein
source in developing countries. Although there are vaccines available for some
forms of this viral disease, they are not effective in all field situations. There
are no effective drugs.
Antibiotics as Growth Stimulants
In some geographic areas, antibiotics are now used extensively in animal
feeds to promote weight increases of young animals. In developed countries,
168
MICROBIAL PROCESSES
the use of such additives is economically important to farmers. When added to
the feed of livestock and poultry in low concentrations (20-50 g per ton of
feed), the animals are healthier, grow more rapidly, and reach marketable
weight faster than those not fed antibiotics.
In the United States, six antibiotics are used extensively for growth-
promoting effects on poultry, swine, cattle, and dairy calves: bacitracin, chlor-
tetracycline, oxytetracycline, monensin, procaine penicillin, and tylosin.
Improved growth rates and feed utilization are in the range of 2-15 percent
for broilers, 2-13 percent for swine, 3-4 percent for beef cattle, and 10-30
percent for dairy calves. Production of these antibiotics by a low-level "non-
sterile" manufacturing process (see below), if one could be developed, would
significantly increase their usefulness as feed supplements by decreasing their
cost.
The complication introduced by the appearance of mutant pathogenic
microorganisms with multiple resistance to broad-spectrum antibiotics has led
to consideration of banning of such feed additives in Great Britain and the
United States. An antibiotic task force has questioned their use in feeds
because of 1) development and dissemination of drug-resistant microorgan-
isms, 2) increased shedding of salmonellae in animal dung, and 3) ingestion of
antibiotic residues in human food, which may cause bacteriological and
pharmacological hazards.
The possible spread of drug-resistant microorganisms through transfer of
extrachromosomal genetic material (DNA) is now of international concern to
scientists and governments. Because of this concern, the use of antibiotics as
food preservatives has already been discontinued in the United States and
England.
Plant Diseases
Hundreds of bacterial and fungal species and a few viruses that cause plant
diseases are known to be suppressed by antibiotics. However, the use of
antibiotics to control plant pathogens is carried out on a large scale only in
Japan. Streptomycin, the tetracyclines, cycloheximide, and griseofulvin have
been used most extensively, but all have serious drawbacks, including plant
toxicity and high production costs Blasticidin S and kasugamycin are widely
used instead of mercurial fungicides to control the sheath blight of rice plants.
These antibiotics are applied at very low concentrations, and the amount
sprayed is 1-10 percent of that of conventional pesticides. This low concen-
tration and the eventual biodegradation of the antibiotics lowers the pos-
sibility of environmental pollution. However, the emergence of resistant
microorganisms reduces the attractiveness of the procedures.
ANTIBIOTICS AND VACCINES
Nonsterile Production of Antibiotics
169
Since the large-scale production of antibiotics requires considerable capital
investment and includes steps (maintenance of cultures, fermentation) that
must be carried out under scrupulously clean conditions, their manufacture in
the developing countries should be considered only in exceptional situations.
To set up low-level, low-cost production of carefully selected antibiotics for
plant or animal disease control might be possible under less rigid conditions
than those currently in use. The production of feed-quality chlortetracycline
on cereal solids, which was developed in Czechoslovakia, is an example of the
potential of this simplified technology.
Vaccines
There are many vaccines available for the prevention of infections in
human beings. They differ considerably in their composition, effectiveness,
and duration of protection. Some are live attenuated viruses; others consist of
whole killed bacteria. Still other preparations consist of viral or bacterial
components or of modified products of bacterial toxins (or toxoids). A list of
diseases for which relatively effective vaccines or immunogenic agents are
available is shown in Table 9.1. The characteristics and future possibilities for
some of these agents are shown in Table 9.2.
Vital statistics obtainable from a number of countries suggest that utiliza-
tion of many of the available vaccines is less than optimal. From the stand-
point of public health and for the welfare of the population at large, it is
important that nations establish effective programs for immunization against
highly communicable infectious diseases. Such programs can be carried out
only if the vaccines are available in adequate supply, with proper facilities
provided for their storage and for protection of their potency, and only if the
public can be educated about the benefits of immunization and a system of
effectively delivering the vaccine can be developed and maintained. Identi-
fication of vaccine failures, especially where the use of live vaccines is con-
cerned, is important in detecting flaws in the methods of vaccine storage or
administration.
Certain vaccines offer a high degree of protection against the diseases for
which they were developed. All children should be protected by immuniza-
tion against measles, whooping cough, diphtheria, tetanus, and poliomyelitis.
There has not been a naturally acquired case of smallpox reported in over a
year anywhere in the world. If the disease is eradicated, then there will no
longer be a need to vaccinate against it. Yellow fever vaccine has also proved
highly effective and should be used in areas where the disease is endemic.
Vaccines of the capsular polysaccharides of meningococcal Groups A and C
170
TABLE 9.2 Current and Future Vaccines and Protective Agents
Current Vaccine
Disease or Protective Agent
Cholera Killed whole organism
MICROBIAL PROCESSES
Possibilities
in 5-10 Years
1. Toxoid vaccine
2. Oral attenuated
3. Oral killed
Diphtheria Toxoid-absorbed Tetanus and diphtheria toxoids
Tetanus Toxoid-absorbed have been effectively used via
Pertussis Killed bacteria or the respiratory tract for
bacterial fraction booster unmunization (con-
cern exists for allergic re-
actions in the lung)
Veal hepatitis
Type A Passive immune Killed or attenuated
serum globulin (ISG) vaccines
Type B Passive immune Specific high-titered
serum globulin (ISG) ISG vaccine
Influenza Egg-grown virus, formalin in- 1. Live attenuated vaccine
activated, highly purified 2. Aerosol killed vaccine-fair
by zonal ultracentrifugation protection, absence of side
effects.
Mumps Vaccine 3. Tissue culture-grown virus
Measles Live attenuated virus,
(rubeola) chick embryo or canine
tissue-culture grown
Plague Formaldehyde-inactivated
Yersinia pestis
Poliomyelitis Inactivated virus
Attenuated virus
monovalent or trivalent
Rabies Active: (1) B-propiolactone- Live attenuated vaccine
inactivated virus grown in
embryonated duck eggs
(2) phenol-inactivated
virus grown in rabbit brain
Passive: equine hyper-
Lmmune serum
Rubella Vaccine
Typhoid Whole organism killed by Oral killed or attenuated vaccines
several different techniques have been tested and seem to
be more effective with fewer
side~ffects
Typhus Formaldehyde-inactivated
Rickettsia prowazekii Dowry
in embryonated eggs
Yellow fever Live attenuated virus prepared
in chick embryo: Dakar
strain or 1 7D strain
Source: Robert H. Waldman. 1978. Immunization procedures. In Clinical concerns of
infectious diseases, L. E. Cluff, and J. E. Johnson, eds. Baltimore: Williams & Wilkins. Co.
ANTIBIOTICS AND VACCINES
171
have been shown to be effective where cerebrospinal meningitis caused b
these organisms is epidemic, and their administration is preferable to that of
prophylactic antimicrobial drugs. To date, a vaccine effective against Group B
meningococcal infection, although needed, has not been developed.
Parasitic and Venereal Diseases
A number of other widespread diseases still lack vaccines that will enable
their eradication or control. These include the parasitic diseases endemic to
many developing tropical countries and the venereal diseases, which are in-
creasingly common throughout the world.
Parasitic Diseases Diseases caused by protozoa and helminths are among
the major scourges of mankind. Malaria, trypanosomiasis, leishmaniasis,
schistosomiasis, and filariasis afflict millions of people. If vaccination against
these and other diseases caused by parasites is contemplated, it will first be
necessary to cultivate the causative organisms and identify the significant cell
components. The recent in vitro cultivation of malarial parasites in the United
States and of the blood form of trypanosomes in Kenya may provide prom-
ising leads in the development of vaccines for these prevalent disorders.
Venereal Diseases Among the venereal diseases, gonorrhea is a major prob-
lem and in many geographic areas the etiological agent of the disease (Neis-
seria gonowhoeae) has become resistant to the action of penicillin. There are
significant gaps, moreover, in our knowledge of this organism and of the
immune response to this infection in humans. Additional research is needed
before a prophylactic vaccine can be developed. Meanwhile, antibiotics other
than penicillin (for example, spectinomycin) may be effective. Syphilis is
amenable to control by case- and contact-finding and by penicillin therapy. A
vaccine effective against genital strains of Herpes simplex virus has distinct
potential utility.
Respiratory Infections
In addition to diseases of childhood spread via the respiratory system
(measles, rubella, mumps), there are many other infections transmitted in this
fashion.
Pneumococcal Infections Of the respiratory infections of bacterial origin,
those caused by pneumococci are most prevalent and are a problem in some
nations where rapid urbanization is in progress. Polyvalent vaccines of pneu-
mococcal capsular polysaccharides are currently available and should prevent
the majority of pneumococcal pneumonias. A similar vaccine for preventing
172
MICROBIAL PROCESSES
respiratory infection and meningitis in young children caused by Haemo-
philus inpuenzoe Type B is under development, but the immune response of
infants to this vaccine has been limited, as has the response to several other
bacterial polysaccharides in children 12-18 months of age and younger. The
need for research on the immunologic responsiveness to vaccines of this kind
in children under 18 months is great.
Bacterial Otitis Media An infection of the middle ear, bacterial otitis
media is prevalent in all societies. If effective vaccines for its prevention could
be developed, the damage to hearing that often results from it could be
eliminated.
Tuberculosis A vaccine of attenuated mycobacteria, scG (Bacille Cal-
mette Guerin strain), has been successfully used against tuberculosis in certain
societies. Some current opinion supports the view that the effect is nonspecific
and that an active public health program of case finding and treatment of
each index case and its contacts is a more effective means of controlling
tuberculosis.
Gastrointestinal Infections
Enteric or intestinal infections exact a terrible toll throughout most of the
world. The World Health Organization estimates that approximately 70 mil-
lion people are afflicted with significant diarrhea! illness during each day of
the year. Intestinal infections may be caused by a wide variety of bacteria,
viruses, and protozoan parasites. They spare no age group, race, nation, or
socioeconomic group. The young, especially infants, are particularly affected.
In many countries diarrhea accounts for 25-50 percent of all infant deaths.
Overall, enteric infection is the leading cause of mortality in most of the
developing world.
Much can be done to eliminate diarrhea! disease by sanitary measures,
including the provision of good water supplies, sanitary disposal of sewage,
and adequate cooking and refrigeration of foodstuffs. In areas where eco-
nomic circumstances preclude such provision, vaccines offer a partially satis-
factory means of preventing some gastrointestinal infection.
Various vaccines have been devised to prevent intestinal illness, and some
have been in use since the latter part of the 19th century. Only in the last two
decades, however, has their efficacy been properly evaluated by controlled
trials. Unfortunately, these trials have shown that the available vaccines
against typhoid fever and cholera are limited in their effectiveness, and there
are no vaccines available for many other causes of diarrhea.
Typhoid Fever Long a scourge throughout the world, typhoid fever runs a
protracted course, causing death in 10-20 percent of untreated victims and
ANTIBIOTICS AND VACCINES
173
prolonged disability in its survivors. A recent outbreak in Mexico affected
thousands of people, demonstrating the continuing threat of this disease.
Vaccines against typhoid fever have been in use since 1895. They consist
of suspensions of killed typhoid bacilli. Side effects are frequent and include
painful swelling at the injection site, fever, and malaise, all of which may
persist for several days.
Because typhoid fever is generally contracted after ingestion of contami-
nated food or water, attempts have been made to stimulate intestinal im-
munity by the oral administration of killed typhoid bacilli. But even when
these were given in twice the recommended dosage, the protective effect was
only 30 percent. A recent attempt at oral immunization involved the use of
attenuated typhoid bacilli. Given in multiple large doses to 155 adult volun-
teers, this live vaccine caused no side effects and protected 87 percent of
individuals from subsequent illness.
Cholera Cholera, which ranks with typhoid as a global affliction, is known
to have spread in pandemic fashion throughout the world on six occasions
during the past two centuries. The seventh pandemic, which is currently
affecting much of Asia, Africa, and the European countries bordering the
Mediterranean, has been caused by a different type of organism, the so-called
El Tor vibrio. The concern caused by the current appearance of the disease is
great. Not only can cholera produce mortality rates of 50 percent and more
in severely affected and untreated individuals, but it may create considerable
panic and economic dislocation throughout a large geographic area.
As with typhoid fever, vaccines against cholera have been in use since the
turn of the century They have generally been composed of killed micro-
organisms administered by one or more injections. Although many claims
have been made as to their effectiveness, field teals have demonstrated that
vaccine efficacy at best was 76 percent during the first 6 months. Protection
waned thereafter, and subsequent booster doses were required. These results
were obtained in a population that had had frequent prior exposure to the
etiological agent of cholera and presumably possessed considerable immunity
prior to vaccination. The vaccine is generally given in mass fashion during
fresh outbreaks, although it has never been shown to have prevented an
. . .
eplaemlc.
Promising results have been obtained with a living attenuated mutant of
the cholera organism given orally to adult volunteers in the United States.
Approximately 60 percent of recipients, given one to four vaccine doses, were
protected from illness after subsequent exposure.
The protective effect of this oral vaccine appeared to be at least equal to
that of the injected vaccines tested in Bangladesh and elsewhere. Indeed, the
efficacy of the oral preparation may be better in a true field situation, where
the effective dose may prove to be substantially lower than that given to the
volunteers of the U.S. study described above. Advantages of the oral product
174
MICROBIAL PROCESSES
are that it avoids the painful side effects of injections and the skill and
expense of administering them.
Present limitations to this oral vaccine are that it is live and produces small
amounts of cholera toxin. Thus the possibility exists that it could revert to a
virulent form. Neither this nor any other oral preparation has yet been field
tested.
Escherichia cold So-called "enteropathogenic" serotypes of E. cold were
first discovered in England in the 1940s. They have been considered to be
associated primarily with epidemics of severe gastroenteritis in hospital
nurseries. Today, many clinical laboratories have the facilities to readily iden-
tify these organisms.
It has been recognized only recently that other varieties of E. colt, termed
"toxigenic" are probably far more important as causative agents of diarrhea!
illness. These organisms are similar to those causing cholera in that a toxin
elaborated by the bacterium causes the illness, rather than the bacterium
itself. They are probably responsible for a significant portion of the familiar
traveler's diarrhea. Although epidemiological investigations are in their in-
fancy, it seems quite likely that toxigenic E. cold play a substantial role in
causing diarrhea throughout the world. Three other bacterial species, Cam-
pylobacter fetus, Yersinia enterocolitica, and Vibrio parahemolyticus, have
been recognized recently as causes of diarrhea! disease in man. No vaccine is
available at present, nor is any mode of therapy definitely established.
Shigellosis Bacterial dysentery, or shigellosis, is an endemic problem in
many areas of the world and frequently flares up in epidemic form. Striking
examples include the large outbreaks in Central America and Bangladesh in
recent years.
Treatment with specific antibiotics (chloramphenicol, ampicillin, or tetra-
cycline) is usually successful, but shigella organisms possess a striking ability
to develop resistance to antibiotic agents. An effective vaccine would be
highly desirable, but none is commercially available.
Viral Diarrhea Various viruses have long been thought to be responsible
for diarrhea! illness. Recent studies have incriminated at least the reovirus and
rotavirus. In some population groups, the latter agent is believed to be respon-
sible for as much as 70 percent of diarrhea! illness in infants. Other studies
have found that young children rapidly acquire antibodies against these
viruses, an indirect indication of the prevalence of infection.
Since work in this area is new, no vaccines are available. With successful
cultivation and propagation of these viruses, however, it is reasonable to
expect that an effective vaccine will be forthcoming.
ANTIBIOTICS AND VACCINES
175
Parasites There are many parasites that may cause significant diarrhea
(Giardia lamblia and Entamoeba histolytica are excellent examples). There is
no imminent promise of a successful vaccine against any of these.
References and Suggested Reading
Anti biotics
Beeson, P. B., and McDermott, W., eds. 1975. Textbook of medicine. Philadelphia-
London-Toronto: W. B. Saunders Company.
Corcoran, J. W., and Hahn, F. E., eds. 1974. Mechanism of action of antimicrobial and
antitumor agents. Antibiotic Series, Volume 3. New York: Springer-Verlag.
Goldberg, I. H.; Beerman, T. A.; and Poon, R. 1977. Antibiotics: nucleic acids as targets
in chemotherapy. In Cancer: a comprehensive treatise, F. F. Becker, ea., Volume 6:
Chemotherapy, pp. 427456. New York: Plenum Press.
Kurylowicz, W., ed. 1976. Antibiotics-a critical review. Warsaw: Polish Medical Pub-
lishers, distributed in the United States of America and Canada by the American
Society for Microbiology, Washington, D.C. 20006.
Lane, M. 1977. Chemotherapy of cancer. In Cancer: diagnosis, treatment and~prognosis,
5th edition, J. A. Del Regato; H. J. Spjut; and J. Harlan, eds., pp. 105-130. St. Louis,
Missouri: C. V. Mosby Company.
Maegraith, B. G., 1973. One world. London: Athlone Press, distributed in the United
States of America by Humanities Press, Inc., Atlantic Heights, New Jersey.
1974. Tropical medicine: trends and progress. Journal of Tropical Medicine and
Hygiene 77:4-7.
Reiner, R. 197 7. Antibiotics. In Methodicum chimicum, Vol. 1 1: Natural compounds,
Part 2: Antibiotics, vitamines and hormones, Fr. Korte and M. Goto, eds, pp. 2-68.
New York: Academic Press.
Woodbine, M., ed. 1976. Antibiotics and antibiosis in agriculture with special reference
to synergism. London: Butterworths.
Zahner, H., and Maas, W. K. 1972. Biology of antibiotics. New York: Springer-Verlag.
Zeigler, E.; Moody, W.; Hepler, P.; and Varela, F. 1977. Light-sensitive membrane poten-
tials in onion guard cells. Nature 270:270-271.
Vaccines
American Academy of Pediatrics. 1974. Report of the committee on infectious diseases.
17th edition. Evanston, Illinois: American Academy of Pediatrics.
Ashcroft, M. T.; Singh, B.; Nicholson, C. C.; et al. 1967. A seven-year field trial of two
typhoid vaccines in Guyana. Lancet 2:1056-1059.
Current status and prospects for improved and new bacterial vaccines. 1977. Journal of
Infectious Diseases 136: Supplement.
Cvjetanovic, E., and Vermura, K. 1965. The present status of field and laboratory studies
of typhoid and paratyphoid vaccines: with special reference to studies sponsored by
the World Health Organization. World Health Organization Bulletin 32:29-36.
Dupont, H. L.; Hornick, R. B.; Snyder, M. J.; et aL 1972. Immunity in shigellosis. II.
Protection induced by oral live vaccine or primary infection. Journal of Infectious
Diseases 125:12-16.
Germanier, R. 1975. Effectiveness of vaccination against cholera and typhoid fever.
Monographs in Allergy 9: 217-230.
Gilman, R. H.; Hornick, R. B.; Woodward, W. E.; Dupont, H. L.; Snyder, M. J.; Levine,
M. M.; and Libonati, J. P. 1977. Evaluation of a UDP-glucose-4-epimeraseless mutant
of Salmonella typhz as a live oral vaccine. Journal of Infectious Diseases
136:717-723.
1
176
MICROBIAL PROCESSES
Gorbach, S. L., and Khurana, C. M. 1972. Toxigenic Escherichia coli: a cause of infantile
diarrhea in Chicago. New England Journal of Medicine 287:791-795.
Hejfec, L. B. 1965. Results of the study of typhoid vaccines in four controlled field trials
in the U.S.S.R. World Health Organization Bulletin 3 2:1-14.
Honda, T., and Finkelstein, R. 1979. Selection and characteristics of a Vibrio cholerae
mutant lacking the A (ADP-Ribosylating) portion of the cholera entero-toxin.
Proceedings of the US National A cademy of Sciences. 76: 205 2-205 6.
Hornick, R. B., and Woodward, W. E. 1966. Appraisal of typhoid vaccine in experi-
mentally infected human subjects. Transactions of the American Clinical and Cli-
matological Association 7 8: 70-78.
Mel, D. M.; Terzin, A. L.; and Vuksic, L. 1965. Studies on vaccination against bacillary
dysentery. 3. Effective oral immunization against Shigella flexneri 2a in a field trial.
World Health Organization Bulletin 32:647-655.
Mosely, W. H. 1969. The role of immunity in cholera. Texas Reports on Biology and
Medicine 27:22?-241.
National Academy of Sciences. 1979. Pharmaceuticals for developing countries: con-
ference proceedings of the division of interrogational health of the institute of medi-
cine. Washington, D.C.: National Academy of Sciences.
Rotaviruses of man and animals: Editorial. 1975. Lancet 1:257.
Sack, R. B.; Hirschhorn, N.; Brownlee, I.; et al. 1975. Entero-toxigenic Escherichia
coli-associated diarrhea! disease in Apache children. New England Journal of Medi-
cine 20:1041-1045.
Shore, E. G.; Dean, A. G.; Holik, K. J.; et al. 1974. Enterotoxin-producing Escherichia
cold and diarrhea! disease in adult travelers: a prospective study. Journal of Infectious
Diseases 129 :577-582.
Waldman, Robert H. 1978. Immunization procedures. In Clinical concepts of infectious
diseases, L. E. Cluff, and J. E. Johnson, eds. Baltimore: Williams & Wilkins Co.
Woodward, W. E.; Gilman, R. H.; Hornick, R. B.; et al. 1976. Efficacy of a live oral
cholera vaccine in human volunteers. Developments in Biological Standardization
33: 108-1 12.
World Health Organization. 1972. Oral enteric bacterial vaccines. Technical Report
Series, No. 500. Geneva: World Health Organization.
Yugoslav Typhoid Commission. 1964. A controlled field trial of the effectiveness of
acetone-dried and inactivated and heat-phenol inactivated typhoid vaccines in Yugo-
slavia: Report. World Health Organization Bulletin 30:623-630.
Source of Cultures
Antibiotics and Vaccines
American Type Culture Collection, 12301 Parklawn Drive, Rockville, Maryland 20852,
U.S.A.
Research Contacts
Antibiotics and Vaccines
Burton Pogell, School of Medicine, St. Louis University, 1402 South Grand Boulevard,
St. Louis, Missouri 53104, U.S.A.
Oldrich K. Sebek, Infectious Disease Research Unit, The Upjohn Company, Kalamazoo,
Michigan 49001, U.S.A.
William E. Woodward, Program in Infectious Diseases and Clinical Microbiology, Uni-
versity of Texas Health Science Center, P. O. Box 20708, Houston, Texas 7702S,
U.S.A.
