VACCINES

Reasons for vaccine exemption:

1. medical (allergic to ingredients in vaccines) allowed in all 50 states
2. Philosophical/ Personal belief (allowed in 20 states)
3. Religious (allowed everywhere but WV and Mississippi)

History of VaccinesViruses


1. Whole Animal Era

Smallpox vaccine was developed by Jenner in the late 1700s. noticed every 2-3 years smallpox
would come to South England and hit about 1/3 of the people and about 1/3 of them would die.
But he heard from someone that milkmaids who got blisters on their hands/wrists, were immune
to smallpox. Because cowpox is antigenically related to smallpox. He took fluid from a
milkmaids blister and put it into a boy.
-Variolation: taking dried up scabs and giving it to healthy people. Were 6-7 times more likely
to not get smallpox.
Jenner realized that if he variolated people who he had given cowpox blister fluid, they didnt
really develop a red sore at the Variolation site. He figured that meant (correctly) that they were
immune to the disease.
-Small pox has been eliminated by worldwide vaccination. Last case was seen in Somalia in
1977.


What did Jenner notice about milkmaids?
When they got blisters on their hands from the cows they were then immune to smallpox
(immunity through exposure to blisters)
What did Jenner do before variolating James Phipps with smallpox?
Injected him with the fluid from the blister of a milkmaid

Rabies vaccine: method of attenuation
-Pasteur grew rabies virus in rabbit spinal cords. Spinal cords were then dried for days or
weeks
-attenuation was by partial killing
-but use of spinal cords (or other nervous tissue) contain myelin, and because its similar
across species you start to have a reaction to the myelin which can have bad side effects. But
because this was a post-exposure vaccine, (and the rabies virus is 100% fatal and the side effects
of the vaccines are only in about 1/200) people still take it even today.

Polio vaccine
Vaccines before Salk (1930s):
-John Kolmar and ricinoleate at Phila gen. hospital
-Maurice Brodie and formaldehyde at NYU
-tragedies using whole brains and spinal cords set polio vaccine research back 20 years. (some
children died from the myelin reaction even though they were perfectly healthy before. This
scared everyone and they didnt want to have that risk with the vaccine)

2. Tissue Culture Era
-Hugh and Mary Maitland, working in Manchester England grow vaccinia virus in chopped up
chicken kidneys. Growing viruses in lab cells is easier than growing viruses in the skin
(smallpox) or spinal cords (rabies and polio) of whole animals.

Yellow Fever Vaccine 1930s first live weakened viral vaccine
Took the technique of being able to grow virus in cells in the lab. Using the Maitlands
technique, Max Theiler took yellow fever virus and serially passaged it in minced preparations of
mouse brains, mouse embryos and chick embryos. He reasoned that serial passage in non-human
cells would attenuate viral growth in human cells. The more he put the virus in animal cells and
the better they got at growing in animals, the worse they got at growing in humans, but still well
enough to induce immunity. This idea of a weakened, attenuated live virus grown in non-human
cells led to many other vaccines. Won the Nobel prize in 1951.


3. Egg Era (current)
Ernest Goodpasture found that viruses could be propagated in the chorioallantoic membrane that
surrounded the chick embryo. Showed that at least 30 viruses grew in eggs which is important
because they are cheap and sterile (which was a big problem before penicillin and such came
around).

Influenza Vaccine (1940s)
Thomas Francis at Michigan found you could inoculate influenza into eggs, treat the virus with
formaldehyde and use that as a vaccine. But this only works for about one year. Francis
propagated influenza viruses in eggs, harvested the allantoic fluid and killed the influenza virus
with formaldehyde. He used Goodpastures technique of growing viruses in eggs and Brodies
technique of killing viruses with formaldehyde.

4. Cell Culture (current)
Polio Vaccine. Polio could be grown in non-neural cells, which goes around the problem of
myelin (see rabies) in the vaccine.
Enders, Weller and Robbins: adapted polio virus to growth in cell culture. Allowed polio virus
to be grown in large quantities. Obviated the need for monkey spinal cords as a source of virus.
Nobel Prize in 1954
Jonas Salk: 3 doses of vaccine given to 420,000 children. 200,000 were inoculated with placebo
and 1.2 million observed, uninoculated. Efficacy was 65% against type 1, 100% against type 2
and 96% against type 3 induced polio. Used Goodpasture/Francis technique. There were some
problems with this vaccine though, because Salk thought that the Formaldehyde was a more
thorough treatment for killing polio than it actually was, about 200 children were paralyzed
because of this and about 10 died because they received live polio virus, not dead. This led to
vaccine regulation.

Measles 1963
-Maurice Hilleman passaged the Edmonston B strain 40 more times in chick embryo fibroblast
cells; called Moraten Strain. Long lived immunity, excellent safety and virtual elimination of
measles in the US.
Mumps (1967)
-Maurice Hillemnan isolated mumps from his daughter. The Jeryl Lynn strain attenuated by
serial passage in chick eggs and chick embryos.
Rubella (1969)
-Maurice Hilleman. Passaged 77 times in monkey kidney cells (still too virulaent);, passaged
then through duck cells.

To make virus: pass the virus through non-human cells so that it is capable of producing an
immune response, but not of making you sick. Separate the part of the virus that makes you sick
from the part of the virus that induces an immune response and is effective. The virus cannot
reproduce itself in human cells anymore, which is how it stays less virulent.

5. Human Fetal Cells (current)

Human fetal cells are useful because they grow anything that can attack humans and because
they are sterile and there is no SV40. They are used to make Rabies, Rubella Varicella dn Hep B
vaccines. 2 of the major cell lines were taken from voluntarily aborted fetuses, one in Philly and
one in England in the early 60s.

6. Whole Blood (1980s)
First Hep B
-Maurice Hilleman took plasma from people infected with Hep B virus (contains whole live
virus and HBsAg) and treated preparation with pepsin urea and formaldehyde to kill the virus.
Only vaccine made using human blood. Strong link between Hep B and liver cancer.

7. Recombinant DNA Era (current)
Second Hep B vaccine:
-Maurice Hilleman took advantage of recombinant DNA technology to make next Hep B
vaccine.
-Stanley Cohen and Herbert Boyer, working at UCSF and Stanford in 1973 found a means to
express non-bacterial proteins in bacterial cells.
-Hillemans hep B vaccine was the first vaccine known to prevent cancer (liver)
Plasmid: small circular dna which can reproduce itself in bacterial cells
Restriction endonucleases: cleave DNA at a specific site.
Use restriction endonucleases to cut the Hep B DNA and put it in the bacteria plasmid where it
can reproduce itself including the Hep B dna

8. Reassortant Viruses
Rotavirus: causes diahrea and vomiting in young children, 2000 children die daily around the
world
Rotavirus genome has 11 separate segments of dsrna, each which codes for one protein.
You can make combo virus (reassort virus) with only a single gene difference and therefore
figure out which gene causes which symptom. If the genes that make you sick are different than
the ones that give you immunity, you can simply engineer a virus that has the genes for
immunity but not for sickness and use it as a vaccine. The other method for rotavirus vaccine is
the more commonly used passing the virus through a series of non-human cells

Viral Vaccines:
limited number of strategies:
-live attenuated virus (measles, mumps, rubella, varicella, OPV, rotavirus)
-whole, killed virus (influenza, rabies, hep A)
-Virus subunit (HBV, HPV)
-Reassortant viruses (rotavirus)

Bacterial Vaccines:
-Once bacteria were grown in broth, many bacterial vaccines were developed in the early 1900s.
-Specifically: S. pneumonia, GABHS, N. meningitides, S. aureus, E. coli, K.. pneumonia and S.
typhi

They would grow the bacteria in broth and treat it with sterilizing agents and use this as a
vaccine. Bacterin (bacterial vaccine). However, they werent effective.

Discoveries that led to vaccines that worked:
-Roux and Yersin find that sterile filtrates of bacteria (diphtheria) can kill animals. This suggests
that a protein (toxin) is produced and secreted by bacteria which can cause harm
-Behring finds that lower levels of toxin injected into animals induces substance that neutralized
toxin activity (antitoxin) Nobel prize
Diphtheria passive vaccine in which you are given antibodies

Diptheria (1920s)
-Ramon in 1920s shows that toxin can be inactivated with formaldehyde and heat. Treatment
eliminated toxicity but preserved immunogenicity. Called it anatoxine, now toxoid.

Tetanus vaccine (1940s)
Tetanus vaccine made using the exact same technology as the diphtheria vaccine. Etry of
American military in WWII

Pertussis vaccine (1940s)
Pertussis has about 3000 structural proteins whole bacterial vaccine
Take bacteria, grow it in broth, purify the bacteria and kill the whole bacteria to make the
vaccine.
Problem with whole bacteria vaccine (when combined with diphtheria and tetanus DTP) they
had very bad side effects. Fever, hypotonic, hyporesponsive, seizures pretty frequently although
the side effects were only temporary. Now we can purify the proteins of the bacteria that induce
an immune response, without the ones that cause the side effects.

Polysaccharide vaccines
-Pneumococcus (sepsis, pneumonia, meningitis)
-meningococcus
-haemophilus influenzae
They would strip the polysjaccharide sugar off.
Problem is that they dont work for young children. Infants are incapable of making B-cell
responses to polysaccharide antigens (t-cell independent B cell responses)
-need to convert polysaccharide response to T-cell dependent B cell response so babies can use
it. So they took the complex sugar and linked it to a protein for babies.

Bacterial Vaccines:
Limited number of strategies
-inactivated toxin (diphtheria, tetanus, pertussis)
-polysaccharide (pneumococcus)
-conjugated polysaccharide (Hib, pneumococcus, meningococcus)

Current Vaccine schedule:
People want to change the schedule because they are scared that:
-children are getting too many vaccines too early fear it causes more autism, ADHD
In 1900 children only got one vaccine, by 1980 they got 5 by the time theyre 2 in 2012
they get 26 by age 2, up to 5 shots at one time.
BUT, fewer immunologic components in vaccines today than 100 years ago.
-Children are too young to be vaccinated
From birth, infants are challenged by bacteria in the environment (colonizing bacteria on
intestines, skin, throat). Vigorous sIgA responses within the first week of life keeps
colonizing bacteria from invading. Babies are already using a huge immune response.
Excellent immune responses to HBV and BCG vaccines given at birth. About 95% of
infants develop protective immune responses to HBV, Hib, DTaP, polio and
pneumococcal vaccines by 6 mo. Need to be fully immunized against certain infections
(Hib, pertussis, pneumococcus) by 6 months.
-Aluminum overload. Used as an adjuvant (lessen number of doses or lessen quantity of
active ingredients. It enhances the immune response). Aluminum is one of the most
abundant elements, its in our food, air, waterfound naturally in teas, herbs, spices and
added to mixes. Also found in breastmilk and infant formula. Aluminum is absorbed
differently when ingested or injected. Almost 100% is eliminated by injection because it
binds to transferrin and is eliminated by the kidneys, about 1% if ingested.
Aluminum is definitely problematic, it can cause encephalopathy, osteomalacia and
anemia in severely premature infants and patients on dialysis, but not really anyone else.
Aluminum is always in our system and checking after vaccines shows no noticeable
increase in aluminum levels
-Too many vaccines at once. Study shows that 2 shots are not more likely to induce
cortisol (as a marker for stress) than one shot.
What is the harm in alternative vaccine schedule?
-not science based
-more likely to induce needle phobia
-increase time during which children are susceptible to vaccine-preventable diseases
-responsibility to the waiting room
-no benefit

Vaccine FAQ

1. What are vaccines? A way of inducing protective immunity that is usually the
consequence of fighting a natural infection without actually getting the infection. (by
taking a protein from the virus, not the whole virus or other manners)
2. Do we still need vaccines? Some viruses/bacteria are still very common, so its still
necessary. There are some others that arent so common, but can and do show up and
can make you very sick or die. If the vaccine is safe, there is not really any reason not to
get the vaccine. Even if a virus/bacteria isnt in America anymore, it can be around in
other countries and people can still be contagious even if they arent showing symptoms.
3. Who recommends Vaccines? CDC, AAP, AAFP look at the data to see whether the
vaccine is useful and if so, in which groups is it most useful.
4. Isnt it better to be naturally infected than vaccinated? No. Natural infection is
dangerous, can lead to suffering or even death. The vaccine is safe and effective.
5. Are vaccines safe? Yes. Medically speaking, safe means the benefits clearly outweigh
the risks.
6. What systems are in place to make sure vaccines are safe? Vaccine adverse events
reporting system (through FDA and CDC) and vaccine safety data link.
7. How do we know different vaccines can be given at the same time? It is required that if
you want to get your vaccine on the schedule, that you prove that your vaccine does not
interfere with any other vaccines.
8. Can I vaccinate my child if he/she is ill? If it is a mild illness, yes. The illness does not
have any adverse effects on the efficacy of the vaccine. But, kids who are really sick,
cannot get vaccines, because there are no definitive studies since kids who are really sick
have so much other stuff going on, its hard to isolate the vaccine variable.
9. Do vaccines cause chronic diseases? Ex: autism, allergies, ADHDstudies have shown
that they do not have any correlation.

Vaccines in the media:
-MMR causes autism was proposed by Dr. Wakefield in 1998. He thought that putting the three
vaccines together made the vaccine less effective and allowed for a virus to travel into the body
and cause autism. He had no proof, he was postulating, but it led to many follow-up studies all
of which proved MMR does not cause autism. But more than 125,000 children in the US did not
get the vaccination which led to outbreaks in the US, in the UK and Ireland there were
hospitalizations and deaths.
The hypothesis shifted to : Thimerosal (in vaccines) causes autism. Again, multiple follow-up
studies show that it does not cause autism. Hyposthesis shifted again, to: too many vaccines
given too soon causes autism. Study shows that on time vaccine receipt in the first year doesnt
adversely affect neuropsychological outcomes.

Defeating Epidemiology
The media can make it look like its a controversy by inviting certain guests even if they arent
experts. Epidemiological studies might possibly miss certain genetically susceptible people.
Anecdotes defeat hard science. Cannot ever accept the null hypothesis, only fail to reject it,
which leaves room for questions and doubt. Cultural biases. Media is for entertainment, not
education. Temporal vs. causal association. Media defends the weak against the powerful.
Media likes mavericks, follow people who are shaking things up even if we dont know if they
are true. Media falls into the single-study trap and doesnt understand science. Easy to scare
people; hard to reassure them.

Rotavirus: a virus that infects the small intestine. Causes fever, vomiting, dehydration
accounts for ~2.7 million cases, 20-60 deaths a year before the vaccine. In developing countries
it is about 500,000 deaths a year, about 2,000 children die every day from rotavirus-induced
dehydration. Vaccine is made using a non-human rotavirus to build up immunity in humans
(like cowpox/smallpox vaccine). But it turns out that the protection is spotty and worked for
kids in some places but not others. Structure: double-layered outer shell around a central core of
dsRNA. Outer layer made of vp4 (P-sensitive to protease which cleaves proteins) and vp7 (G-
glycoprotein) neutralizing surface proteins. 11 separate segments of dsRNA.
Functional properties of rotavirus proteins:
-vp4 (P type) and vp7 (G type) each independently evoke antibodies that neutralize
rotavirus infectivity
-prevalent G and P types include G1, G2, G3, G4, G9 and P1
-4 genes required for virulence. Advance beyond Theilers attenuation.