Antibiotic resistance has reduced treatment options for infectious diseases, but vaccines have been highly successful at preventing disease without pathogens developing resistance. Vaccines work by eliciting a specific immune response, whereas antibiotics non-specifically kill microbes, allowing resistance to develop. While antibiotic use is necessary, overuse has accelerated resistance development. Increased vaccine coverage and development of new vaccines offer the best strategy to control infectious diseases without resistance issues.

1. Vaccine Victories Against
Microbial Resistance
Antibiotic resistance is reducing therapeutic options for
infectious diseases – the cause of the most common and
difficult acute medical conditions – but, perhaps, a solution
can be found in re-examining previous successes
Dr Donald F Gerson, Jonas Elliott
Gerson, Allison Turner, and Dr
Gail Meadows at PnuVax
Over the last century, humans were winning the war against
microbes, and both antibiotics and vaccines have greatly
reduced death and illness due to infectious disease, eliminating
or quickly curing many once-common life-threatening diseases.
Both antibiotics and vaccines have become indispensable to
medical practice. However, microbes are now resurging by
developing antibiotic resistance. Pneumococcal pneumonia
was successfully treated with penicillin and other antibiotics
for decades, but antibiotic resistance emerged as a significant
problem in the years before 2000. When the highly effective
pneumococcal conjugate vaccine was introduced, it reduced
disease incidence in the children of routinely immunised
countries, but left many low-income children unprotected
and susceptible to antibiotic-resistant infections. For instance,
in Saudi Arabia, before the pneumococcal conjugate vaccine
was introduced, 59% of streptococcal isolates were found to
be penicillin resistant, and 14% were highly resistant (1).
Growing Problem
Antibiotic resistance results in the deaths of about 700,000
people annually, a number that is steadily growing (2). This is
a problem even in wealthy countries with excellent healthcare
systems, such as the US, where about two million antibiotic-
resistant infections occur every year, with about 1 in 100
resulting in death (3).
The problem is not restricted to location or pathogen type,
and some‘extensively drug-resistant’types of most common
pathogens now exist. Some pathogens can be effectively
prevented by vaccination, but even with these – such as
pneumococcal pneumonia – in areas of low vaccine coverage,
children can suffer from antibiotic-resistant strains. However,
‘vaccine resistance’is never seen in strains for which a vaccine
has been developed.
While pneumococcal pneumonia remains one of the greatest
killers of children under five years of age, is the combined
approach of antibiotic and vaccine the model to follow for the
future?What is the biological basis for the rise in the antibiotic
resistance of pathogens, and what are the best strategies to
recover from the gradual loss of effectiveness of these powerful
therapeutics?What is the best interplay between antibiotics and
vaccines to provide the best control of infectious diseases in the
human population?
To answer these questions, the massive intersection of biological
phenomena that is occupied by microbial pathogens, antibiotic
agents, and the human immune system must be examined.
Around 1,400 human pathogens exist: bacteria, viruses,
yeast, fungi, protozoa, and small multicellular organisms.
There are now 15 classes of over 100 individual antimicrobial
antibiotics, and 13 classes of antiviral drugs with about 90
approved products. Most are wide-spectrum and, thus, are
able to kill a range of pathogens. These have resulted from
many decades of massive pharmaceutical efforts and
expenditures on R&D activities, clinical trials, and regulatory
approvals. Most antibiotics are inexpensive, plentiful, and
highly effective at treating disease, resulting in high rates of
use. Over the past decade, antibacterial antibiotic production
and sales have remained static in spite of concerns about
antibiotic resistance in developed nations (see Figure 1).
However, in recent decades, the return on investment has
dwindled while required investment has risen sharply,
reducing the business to a steady state, with low rates
of introduction of now urgently needed new antibiotics.
Addressing the Issue
Adding to the problem, sometimes antibiotics are used
with poor targeting, overdosing, and inconsistencies.
The War Against Microbes
January 201910
Image:©Pixabay

2. The effect of ineffective use is that a fraction of the population
of pathogens in a given person are killed, while the
resistant remainders survive, selecting mutant pathogen
strains that tolerate ever-increasing antibiotic dosages, and
multi-drug resistance follows the same pattern. An infected
person may contain several billion pathogen organisms, and,
if only a small fraction is resistant to the inadequate dose,
then millions remain that are resistant to the antibiotic, and
these multiply, spreading to others. Repeated, this generates
a population of antibiotic resistant pathogens that cannot
be killed, and, because the antibiotics then do not work,
patients die. A multitude of mechanisms are available for
developing antibiotic resistance that frequently arise from
incremental single nucleotide mutations, leading to amino
acid substitutions that successively and increasingly enhance
or protect the proteins involved in antibiotic action (4).
After all, antibiotics are largely natural products derived
from defensive compounds microbes have evolved to
produce so that they reduce competition in their original
wild habitats. Counter-evolution by the natural antibiotic
targets has conferred the basic ability in many microbes to
evade, destroy, or excrete antibiotics. With sufficient selection
and large numbers, strains evolve that may be impervious
to all known potentially effective antibiotics. The situation
is being approached with tuberculosis, some streptococcus
and staphylococcus, and Neisseriagonorrheae. Many of these
antibiotic-resistant organisms are ones for which no vaccine
or other effective treatment is available.
Further exacerbating the problem, microbes are adept at
‘picking up’genes from one another. The first well-studied
natural example of this was discovered by Avery in the early
1900s in Streptococcus pneumoniae, and antibiotic resistance
genes are commonly passed between pathogenic species on
plasmids by this kind of mechanism. Recent and significant
examples are Escherichia coli O175:H7 that contains Shiga
toxin, leading to acute kidney failure and, often, death, and
examples of Neisseria meningitidis serogroup B that acquired
genes conferring ciprofloxacin resistance by horizontal transfer
Figure 1: Sales by antibiotic type
Across practically all types of antibacterial antibiotics, sales have been relatively static over the past decade in Japan, US, France, Italy, Germany, Spain, and the UK, in
spite of increasing concerns of antibacterial antibiotic resistance
All other antibacterials
All other classes
Aminoglycosides
Broad spectrum penicillins
Carbenicillin and similar types
Cephalosporins
Fluoroquinolones
Glycopeptide antibacterials
Macrolides and similar types
Medium/narrow-spectrum
penicillin platform
Medium/narrow-spectrum penicillins
Penems and carbapenems
Polymyxins
Tetracyclines and combs
Trimethoprim combs
Antibacterial antibiotics market (US $,‘000s)
Class
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Market
Year
Several notable pathogens have co-evolved to frequently
escape pre-existing immunity through complex evolutionary
predator-prey mechanisms involving many cycles of infection
between different species
Source: Datamonitor

3. from the non-pathogenic commensal Neisseria lactamica (5).
These mechanisms of genetic transfer are responsible
for a significant fraction of the increases seen in antibiotic-
resistant pathogens. Antibiotics are also highly effective at
increasing feed conversion in farm animals raised for food.
Part of the benefit is due to disease control, but is also due
to the effects of antibiotics on the animal’s microbiome,
leading to greater efficiency in converting food materials
to body mass. The consequence has been a massive use
of antibiotics in food production as an inexpensive way to
increase animal-derived food production efficiency. Large
numbers of antibiotic-resistant microbes arise from this
practice, and, even if the original organism is not a human
pathogen, it may pass on antibiotic-resistant genes to
human pathogens. Non-prescription antibiotics are
produced at around 280 tonnes per hour worldwide, far
exceeding human use for disease treatment (6). Reducing
antibiotic use in food production is a critical component in
overcoming the global antibiotic resistance problem.
The net effect of these and other mechanisms developing
antibiotic resistance in human pathogens has resulted in
the emergence of highly resistant forms of Mycobacterium
tuberculosis, staphylococcus, streptococcus, gonorrhea,
syphilis, pathogenic Ecoli, typhoid, HIV, and a multitude
of others. Antibiotic resistance is now a global problem
and must be addressed in ways that consider the entire
problem in all of its aspects.TheWHO has convened
multiple groups to address this problem (7).
Over the same century that antibiotics have been used,
the worldwide use of pathogen-specific vaccines has also
risen, with quite the opposite effect: no pathogens become
resistant to their specific vaccines. Tetanus and diphtheria
vaccines have been in widespread use for about a century,
primarily focussing on immunity to toxins produced by
these organisms, yet, there are no new vaccine-resistant
strains of these life-threatening pathogens. What is the
difference and what can be learnt from vaccine success
to change the antibiotic outcome?
The human immune system is incredible, with multiple
interacting mechanisms of host defence, pathogen killing,
internal amplifications and controls, memory, and multiple
safeguards against self-directed actions. A single person’s
immune system routinely produces billions of different
kinds of antibodies each day, self-selects those that bind a
pathogen currently present in the system, and immediately
and specifically expands the production of those antibodies
that are needed for active defence. The immune system can
manufacture about 1g of pathogen-specific antibody to a
specific target in a day. Amazingly, each person is their own
antibody factory, a factory that far exceeds the capabilities
of the global pharma industry. Cells modified to produce
monoclonal antibodies can be used in production systems
to manufacture up to 10kg of antigen-specific antibody per
week, allowing the treatment of large numbers of individuals.
Antibodies and the immune system kill pathogens in quite
a different way to antibiotics. Antibodies bind with high
specificity to a specific molecular motif, or‘epitope’, on a given
pathogen, coating or opsonising the target with antibodies
in such a way that phagocytic cells engulf the opsonised
pathogen, encapsulate it, kill it with a variety of reactive
oxygen species and enzymes, and then dispose of the non-
toxic, non-infective residue. Typically, a person may carry
many hundreds of different antibodies to a specific pathogen,
making small genetic mutations in one or another of the
pathogen’s proteins insignificant to the overall effectiveness
of the immune response, so practically no pathogens can
evade a properly immunised person.
Certain bacterial pathogens have developed‘serotypes’
that are immunologically exclusive; immunity to one
serotype does not confer immunity to another. These
result from much more complex genetic changes in
the organism than are required for antibiotic resistance
and are developed by long-term competitive interactions
with the human immune system. Serotypes are relatively
stable, arise slowly, and are often of essentially global
distribution. S pneumoniae, other streptococci, and
several other pathogens have developed large number
of serotypes, each with its own prevalence. Vaccines
for S pneumoniae available today contain antigens for
23, 13, and 10 serotypes respectively, preventing almost
100% of serotype-specific infections and between 95%
and 85% of all infections due to this species. Serotypes not
reduced by vaccines, because either immunisation coverage
is poor or they are not in the vaccine, become the main
pool from which antibiotic resistance can develop. High
immunisation rates and increased numbers of serotypes
in vaccines should provide the best way to reduce first
antibiotic use and then antibiotic resistance to vanishing
levels in these pathogens.
Several notable pathogens have co-evolved to frequently
escape pre-existing immunity through complex evolutionary
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Image:©CDC/SarahBaileyCutchin

4. Dr Donald F Gerson is President and
CEO of PnuVax and has many years’
experience in vaccine and biopharmaceutical
manufacturing management. He is the
former President and Chief Operating
Officer of Celltrion and was also previously
Managing Director for manufacturing at Wyeth-Lederle
Vaccines and Pediatrics. Donald has produced many
vaccines to prevent and treat bacterial infections, as well as
experimental vaccines for HIV and other diseases. He has
founded many biotechnology companies around the world
and has a PhD in biophysics from McGill University, Canada.
Email: dongerson@pnuvax.com
Jonas Elliott Gerson is co-founder and
Director of Operations at PnuVax. He
oversees vaccine manufacturing operations,
including those
for pneumonia and yellow fever. He has a
MASc in chemical engineering from Queen’s
University, Canada.
Email: jonasgerson@pnuvax.com
Allison Turner is co-founder and Director of
Product Development at PnuVax. She leads the
vaccines R&D team with a focus on pneumonia.
Allison held academic research and teaching
appointments until joining PnuVax in 2008.
Allison has a MASc in chemical engineering
from Queen’s University, Canada.
Email: allisonturner@pnuvax.com
Dr Gail Meadows is Head of Compliance at
PnuVax and has many years of experience
in industrial vaccine and biopharma R&D,
validation and quality systems. She has a PhD
fromtheUniversityofWesternOntario,Canada.
Email: gailmeadows@pnuvax.com
About the authors
predator-prey mechanisms involving many cycles of
infection between different species. Most notable is
influenza, which cycles between human, bird, and, often,
porcine, hosts over yearly intervals to annually create a new
variety that can thrive in previously immunised humans.
Influenza has also developed a complex mechanism for
evading mammalian immunity by initiating ineffective
immune responses, and, to date, cross-serotype vaccines
have not been discovered. Also, with influenza, increased
immunisation will decrease incidence, which will reduce
interspecies cycling, thus decreasing the generation of
novel serotypes. Separation of humans and animal carriers
of influenza, improved agricultural and human hygiene
conditions, and additional suppression by antiviral drugs
when needed may be the practical means of creating a
downward spiral in influenza.
Of course, several troublesome organisms remain, for
which antibiotic effectiveness is, at best, low. Antibiotic
resistance is rising, and vaccines or other immunological
treatments have eluded discovery. Mycobacterium
tuberculosis heads the list in terms of global numbers
and Staphylococcus aureus in terms of acute severity.
Various enterobacteria, N gonorrhoeae, Acinetobacter
baumanii, and many others have eluded vaccine
development to date and require urgent and focussed
efforts. Viral pathogens lacking vaccines, such as HIV,
have demonstrated the value of combination antiviral
products that reduce the odds of escape mutants to levels
below the number of organisms in a given patient, but
also have evaded vaccine development to date. Fungi and
multicellular pathogens have also eluded highly effective
antibiotic, vaccine, or therapeutic antibody development.
Antibiotic resistance is the inevitable result of normal
evolutionary pressures on living organisms; the small
fraction of the population that survives treatment
becomes the next generation and is ever more resistant
to the treatment. While humanity may desire the extinction
of certain pathogens, it is difficult. To date, only smallpox
and rinderpest have been eliminated, and, perhaps, polio
will soon follow. In all cases of immunisation, harnessing
the immense multimodal power of the human immune
system was the effective method. The more practical
solution is to continue to develop orthogonal approaches
and develop new small molecule antibiotics, vaccines, and
therapeutic antibodies for each troublesome pathogen. In
the future, bacteriophages and competition by genetically
modified organisms will add to the list of tools available to
ameliorate and reduce human disease.
Humans are definitely winning the war against microbes,
but there many intensely focussed battles remain ahead.
References
1. Memish Z et al, Streptococcus pneumoniae in Saudi
Arabia: Antibiotic resistance and serotypes of recent
www.samedanltd.com 13
clinical isolates, Intl J Antimicrob Agents 23(1):
pp32-8, 2004
2. Visit: prosyn.org/hU5lXPw
3. Hampton T, Report reveals scope of US
antibiotic resistance threat, JAMA 310(16):
pp1,661-3, 2013
4. Blair JMA et al, Molecular mechanisms of
antibiotic resistance, Nat Rev Microbiol
13(1): pp42-51, 2014
5. Wu H et al, Emergence of Ciprofloxacin-Resistant
Neisseria meningitidis in North America, N Engl
J Med 360(9): pp886-92, 2009
6. Morgan DJ et al, Non-prescription antimicrobial
use worldwide: A systematic review, Lancet Infect
Dis 11(9): pp692-701, 2011
7. Visit: who.int/en/news-room/fact-sheets/detail/
antibiotic-resistance