jaishree s msc medical microbiology university of madras

1. WHY DOES DRUG RESISTANCE
READILY EVOLVE BUT VACCINE
RESISTANCE DOES NOT?
JAISHREE.S
II M.Sc MEDICAL MICROBIOLOGY

2. INTRODUCTION
 A vaccine is a biological preparation that provides active aquired immunity to a
particular disease. It contains an agent which resembles a disease causing
microorganism and its often made from weakened or killed forms of a microbe,
its toxins or one of its surface proteins.
 The terms vaccine and vaccination are derived from Variolae vaccinae (smallpox
of the cow) – Edward Jenner.
 A vaccine helps the body’s immune system to recognize and fight pathogens like
viruses or bacteria, which then keeps us safe from the diseases they cause.
 WHO(2019) reported that vaccination prevents 2-3 million deaths each year.

3.  Drugs are the substances which has a physiological effect when ingested or
introduced into the body.
 Drug resistance is the reduction of effectiveness of a medication in treating a
disease. It is due to over prescription of antibiotics, or patient not finishing the
entire antibiotic course, misuse of antibiotics,, and so on.
 Drugs and vaccines both impose substantial pressure on the pathogen
population to evolve resistance and indeed drug resistance typically emerges
soon after the introduction of the drug. But vaccine resistance has only rarely
emerged.

4. vaccine
Live attenuated Inactivated Subunit(purified) Toxoid
VACCINEANDITSTYPES:
 Tuberculosis
 Oral polio
 Measles
 Yellow fever
 rotavirus
 Whole cell pertussis
 Inactivated polio
 Haemophilus
influenzae - B
 Pneumococcal
 Hepatitis B
 Tetanus toxoid
 Diphtheria toxoid

5. DRUGS VACCINES
Therapeutically Prophylactically
specific metabolic pathway Multitarget
• Multiple 1. Antigen
2. Epitopes
•Immunity itself act like combination
therapy with more component effector
Resistance readily evolves invitro that
minimizes spatial variation in drug
dose
Induce systemic host responses that may
minimize spatial refugia and spatial
heterogeneity within hosts.
Resistance-Rare
Population size has already reached the
transmissible state.
Indirectly reduces the pathogen
population size through herd immunity.
Drugs remain active in environmental
reservoirs and also within the hosts.
Vaccines are active only while the
pathogens are inside the hosts.

6. How Vaccines Works
Vaccine containing antigen
Stimulates antibody against pathogen
After vaccination, the pathogen when exposes for
the first time, which contain antigenic features
similar to the vaccine, there is quick defense against
it.

7. S.No Vaccine Prevents I Dose I-II Dose II-III Dose III-IV Dose IV-V Dose
1 BCG TB & bladder cancer Birth
2 HepB Hepatitis B Birth 4 weeks 8 weeks
3 Poliovirus Polio Birth 4 weeks 4 weeks
4 DTP Diphtheria, Tetanus & Pertussis 6 weeks 4 weeks 4 weeks 6 M(Booster 1)
3 years
(Booster
2)
5 Hib Bacterial infection 6 weeks 4 weeks 4 weeks 6 M (Booster 1)
6 PCV Pneumonia 6 weeks 4 weeks 4 weeks 6 M (Booster 1)
7 RV Diarrheal Disease 6 weeks 4 weeks 4 weeks
8 Typhoid Typhoid Fever
9
months
15 months
(Booster 1)
9 MMR Measles, Mumps & Rubella
9
months
6 months
10 Varicella Chickenpox 1 year 3 months
11 HepA Liver disease 1 year 6 months
12 Tdap Diphtheria, Tetanus & Pertussis 7 years
13 HPV Some Cancers & Warts 9 years
Age: 9-14 years:
6 months.
Age: 15 or more: 1
month
Age- 15 or
more: 5
months
IMMUNIZATION SCHEDULE - 2020

8. Vaccine resistance
vaccine resistance is the reduction in
effectiveness of the vaccine.
Natural
evolution
Pathogen
evolution

9. PATHOGEN EVOLUTION
 The evolution of bacterial pathogenicity, it is mainly by the tremendous evolutionary
pressure for resistance.
The evolutionary changes includes
 serotype replacement
(similar to the opportunistic infection caused by Clostridium difficile appearing
after drugs were used to treat a different pathogen)
 novel serotypes
 antigenic loss
 antigenic drift
Vaccines generally provide sustained disease control, the evolution of vaccine resistance
is so rare that vaccines are now considered a leading solution to the drug resistance
problem.
Pathogen evolution always undermines drugs but rarely undermines vaccines. For
example, it is common to associate drugs with bacterial diseases and vaccines with viral
diseases, and might wonder bacteria evolve more resistance than virus. But that cannot be
a general explanation; viruses rapidly evolve resistance to antiviral drugs.

10. EVOLUTION OF DRUG AND VACCINE RESISTANCE

11. Hepatitis B
Shortly after the introduction of vaccination, mutant strains of Hepatitis B Virus
were observed in vaccinated hosts.
The first reported case of vaccine resistance occurred in Italy.
Series of study was conducted in Taiwan, sequencing of Hepatitis B viruses was
performed which infected the children, reported that prevalence was due to
‘escape mutants’ which has the ability to escape antibody detection and antibody
neutralization.
These escape mutants may lead to reinfection with Hepatitis B Virus.
Currently the use of Recombinant vaccines has successfully reduced the disease
incidence.

12. Pneumococcal conjugate vaccine
The human pathogen Streptococcus pneumoniae has shown evidence of evolution
after the introduction of Pneumococcal conjugate vaccine.
Scientists till now have discovered more than 90 distinct serotype for Streptococcus
pneumoniae .
First they targeted 7 serotypes(prevnar 7), and completely eliminated infections with seven
targeted serotypes but other rarer serotypes caused disease.
The vaccine resistance in this vaccine is mainly by serotype replacement.
Ongoing vaccination for streptococcus pneumoniae is PCV13.

13. Bordetella pertussis
 Initially, this evolution appeared consistent with strain replacement, where
strains of pertussis dissimilar to vaccine strains increased in frequency.
First whole cell vaccine was used that gained resistance hence acellular vaccine
are now in present vaccination procedures. Acellular vaccines protect against
disease, but may not prevent infection and transmission.
 After the introduction of acellular vaccine, strains of pertussis that did not
produce pertactin(immunogenic virulence factor)
Consistent with the expectation of vaccine-driven evolution, pertactin-negative
strains were more common in vaccinated than unvaccinated patients.

14. VACCINE RESISTANCE
-Absence Of Vaccine Resistance
1.Measles
Frankandbush-tradeoffbetweenrapidpathogentransmissionandantigenicflexibility
kallandetal.-unusuallylowmutationrateforRNAvirus
schragetal-mutatesatratessimilartothatofRNAvirus
therefore,antigenicconstraintmightbethepropertyofmeaslesvirus,itisnotaninherent
propertyofvaccinetargets.
2.Polio&Smallpox
naturalimmunitywhichpathogenevolutionfailedtoevadedespiteofintenseselectionfor
thousandsofyears(childhooddiseases)becausetheyarebroadlycrossreactive.
-RESISTANCEAND THEIR FACTORS
therearetwokeyfactorstheyare
1.timingofaction
2.multiplicityoftherapeutictargetswithandbetweenhosts

15. 1. TIMING OF ACTION
 Pathogen replication during this incubation period creates opportunities for
mutations to arise , while pathogen transmission after this incubation period
creates opportunities for mutations to spread to new hosts.
 Drugs are administered therapeutically, (after the symptoms arise).
at this therapeutic treatment, the pathogen population within the host can
be enormous , already accumulated genetic diversity and become
transmissible.
 Larger the microbial population at the time of treatment the more likely the
evolution of drug resistance.
 Vaccines keeps the pathogen population from achieving larger sizes,
reducing the accumulation of diversity and onward transmission.
 Therefore, prophylactic nature of vaccines reduces the opportunities for
resistance to emerge and spread.

16. Pathogen Population size
in an untreated host.
Later treatment
(drugs)
EFFECT OF TREATMENT TIMING ON THE EVOLUTION OF
RESISTANCE IN A SINGLE INFECTION
Early treatment
(vaccine)

17. 2. MULTIPLICITY OF THERAPEUTIC TARGETS
WITHIN AND BETWEEN HOSTS
The evolution of resistance may be slowed by therapeutic redundancy, where microbial
population is controlled in multiple efficacious ways. They are:
Combination Therapy
Simultaneous use of different drugs to same host.
Benefit: resistance only occurs when there is simultaneous acquisition of resistance for
each component drug.
example: HIV, Tuberculosis
It prevents the within host evolution of drug resistance, when patients are fully compliant.
For example, influenza virus evolved resistance to monoclonal antibodies, resistance was
reduced when the different monoclonal antibodies were used simultaneously

18. Treatment Mosaics
Simultaneous use of different drugs in different hosts.
Benefit: create heterogeneity in selection.
It will slow or prevents the spread of resistance., once it has emerged
For example, approximately 100 unique tetanus-toxoid-specific antibodies
can be observed in healthy humans after receiving a tetanus-toxoid booster
vaccine, with these antibodies being unique between subjects. The high
multiplicity of therapeutic vaccine targets thus reduces the chance that
resistance will originate and the ability of resistance to spread

19. Classical example for vaccine resistance
Marek’s disease(Gallid herpes virusII)
 highly contagious, paralyzing and ultimately deadly disease affecting chickens and
poultry industry.
 Marek’s disease has been sickening chickens globally for over a century; birds catch it
by inhaling dust laden with viral particles shed in other birds’ feathers.
 Two generations of vaccines were undermined by viral evolution. Those vaccines
prevented disease but even before the pathogen evolved.
 But they did not prevent the viral replication, infection and transmission. Hence this
virus reached large population size in vaccinated hosts and vaccine induced selection
was able to act during the transmission between the hosts.
 The benefits of prophylaxis were thus missing.
 The first vaccine was introduced in 1970, when the disease was killing entire flocks.
Second vaccine introduced in 1983, currently on third vaccine. Fourth vaccine is on line

20. CONCLUSION
1. Drugs are used therapeutically whereas vaccines are used prophylactically.
2. Drugs attack fewer target sites, but vaccine multitargets.
3. Vaccines prevent infection and transmission and induce immunity against many
pathogen target sites, hence hard the evolution of vaccine resistance.
4. The 2 main key factors for vaccine resistance is
 Timing Of Action
 Multiplicity Of Therapeutic Targets.
5. Other features of drugs and vaccines are likely to have at their best only
moderate or system specific effect on the rate of resistance evolution.
6. Host immune system have been shaped by coevolution between pathogen and
hosts. Microorganisms have been coevolving with drug effectors long before the
medical use of drugs and vaccines.

22. RECENTUPDATES
 Measles deemed to be eliminated in 2000
because of vaccination success. Re-
emergence has been associated with
resistance to vaccination.
 (large measles outbreaks such as in
ukraine, philiphines and israel).
 This occurred – when an unvaccinated
individual visits an endemic measles
area, returned back home, children tends
to develop infection.

23. How Vaccines Resistance Works
Natural Evolution
time
time
Vaccine effective against antigens on
targeted pathogens
Random mutations
Vaccine loses its effectiveness
against pathogen population
Key
1. Random
mutations
2. Effective vaccine
antibody
antigen

24. Vaccine-Driven Evolution
time
time
vaccine
vaccine
Pathogen Antigens
Antigen on survivors
Surviving population expands
Antigen on survivors
Pathogen less vulnerable to vaccine
Key
1. Pathogen antigens
2. Survivors