Tag: development

Vaccine Testing and Development Timeline and Myths

New vaccines must go through a long journey before they are finally approved by the FDA and get added to the recommended immunization schedule.

vaccine-dev-testing

Vaccine Testing and Development Myths

There are many myths and much misinformation surrounding vaccine testing and development that is used to scare parents away from vaccinating their kids.

Have you heard that vaccines aren’t tested together?

Or that flu vaccines or Tdap were never tested on pregnant women?

Then there are the myths about fast-tracking, and that important steps are skipped when a vaccine is on fast track for FDA approval, or that the whole vaccine testing and development process happens very quickly.

Vaccine Testing and Development Timeline

The vaccine development process is anything but quick.

“Vaccine development is a long, complex process, often lasting 10-15 years and involving a combination of public and private involvement.”

The History of Vaccines on Vaccine Development, Testing, and Regulation

During this time of the exploratory and pre-clinical stage research and then phase 1,2, and 3 trails, vaccines are:

  • tested on animals
  • tested on small groups of people
  • tested on larger groups of people
  • tested alone
  • tested together with other vaccines
  • tested for safety
  • tested for efficacy (to make sure they work)

This often includes double-blind, placebo controlled vaccine trials.

Fast tracking does speed the process up, but not because any of the testing is skipped. The researchers just get more frequent meetings and communication with the FDA and “Eligibility for Accelerated Approval and Priority Review, if relevant criteria are met.”

“Vaccine development is a complex multidisciplinary activity, combining understanding of host-pathogen interactions at the molecular level, with clinical science, population-level epidemiology and the biomechanical requirements of production.”

Anthony L. Cunningham, et al on Vaccine development: From concept to early clinical testing

Testing doesn’t stop once a vaccine is approved by the FDA and is added to the immunization schedule either. We often continue to see testing for vaccine safety and efficacy using phase 4 trials and with our post-licensure vaccine safety system, including VAERS and the Vaccine Safety Datalink.

And of course testing continues long after we begin using vaccines to see how long their protection will last. For example, because of continued testing, we now know that Gardasil and Cervarix are providing protection that lasts at least 8 and 9 years.

What To Know About Vaccine Testing and Development

From pre-clinical studies and years of phase 1, 2, and 3 trials to continued monitoring after a vaccine is approved and added to the immunization schedule, the vaccine testing and development process helps make sure that vaccines are safe and that they work.

More About Vaccine Testing and Development

Vaccine Timeline and History of Vaccines

Most people are aware of the big historic dates and events related to vaccines.

For example, they might now when Edward Jenner first tested his smallpox vaccine (1798), when the first polio vaccine was licensed by Jonas Salk (1955), or that we just got a Meningococcal B vaccine (2014).

Smallpox was officially declared to have been eradicated in December 1979.
Smallpox was officially declared to have been eradicated worldwide in December 1979.

But few likely now that we have had rabies vaccines since 1885, a flu vaccine since 1945, or that the last case of wild polio in the United States was in 1979.

“It is hard to fully appreciate how vaccines have revolutionized modern medicine. The long schedule of vaccines may seem like a hassle, and rumors about harmful effects unnerve parents. But, the fact is, vaccines have helped save millions and millions of lives. Just a few generations ago, people lived under the constant threat of deadly infectious diseases, like smallpox, polio, and hepatitis.

Let’s look at the greatest infectious scourges of the past 1,000 years and how vaccines have mitigated or even eradicated the danger.”

Public Health Understanding Vaccines

From historical safety concerns, like the Cutter Incident in 1955 or the withdrawal of the first rotavirus vaccine in 1999, to improvements in vaccine safety and the control, elimination, and eradication of vaccine-preventable diseases, understanding the history of vaccines can help you get educated and understand that vaccines work and that they are safe and necessary.

Early History of Vaccination

In the early history of vaccination we had the the smallpox vaccine and the beginning of the pre-vaccine era – the first vaccines.

  • Lady Mary Wortley Montagu brings variolation to England to prevent smallpox
  • George Washington mandated that every soldier in the Continental Army had to be inoculated against smallpox
  • Edward Jenner conducts experiments in 1796 that led to the creation of the first smallpox vaccine a few years later and replaces variolation as a preventative for smallpox
  • *Dr. Luigi Sacco becomes the Jenner of Italy
  • James Madison, one of the Founding Fathers, signed the Vaccine Act of 1813 – An Act to encourage Vaccination.
  • a vaccine for rabies is developed by Louis Pasteur in 1885
  • vaccines for cholera and typhoid were developed in 1896 and a plague vaccine in 1887
  • the first diphtheria vaccine is developed in about 1913 through the work of Emil Adolf Behring, William Hallock Park, and others
  • the first whole-cell pertussis vaccines is developed in 1914, although it will take several decades before they are more widely used
  • a tetanus vaccine is developed in 1927
  • 12 children die when a multi-use bottle of diphtheria vaccine that didn’t contain a preservative became contaminated with bacteria in the Queensland Disaster in 1928
  • Max Theiler develops the first yellow fever vaccine in 1936
  • the AAP formally approves the use of a pertussis vaccine created by Pearl Kendrick and Grace Eldering in 1943
  • the first flu vaccine is licensed for use in the US in 1945

End of the Pre-Vaccine Era

In the mid-20th century, we started to get vaccines to control diseases that many of us have never seen, like polio, measles, and rubella.

  • the individual diphtheria, tetanus, and pertussis vaccines become combined in a single DTP vaccine in 1948
  • the last smallpox outbreak in the United States kills one person, Lillian Barber, in the Rio Grande Valley of South Texas in 1949
  • the Salk inactivated polio vaccine (IPV) is introduced in 1955
  • President Dwight D Eisenhower signed the Polio Vaccination Assistance Act in 1955, which gave $30 million in federal grants to states to cover the costs of planning and conducting polio vaccination programs, including purchasing polio vaccine
  • about 200 children develop polio in 1955 from contaminated polio vaccines in what becomes known as the Cutter Incident
  • the live, oral Sabin polio vaccine (OPV) replaces the Salk polio vaccine in 1962
  • President John F Kennedy signed the Vaccination Assistance Act in 1962 (Section 317 of the Public Health Service Act), which started as a three year program to help get kids vaccinated against polio, diphtheria, tetanus, and pertussis, but it has been continuously reauthorized ever since
  • the first live measles vaccine was licensed in 1963 but was replaced with a further attenuated measles virus that caused fewer side effects in 1968
  • President Lyndon B Johnson established a legacy of US leadership in global immunization by funding the CDC Smallpox Eradication program in 1965
  • the MMR vaccine becomes available in 1971, combined the vaccines for measles, mumps (licensed in 1967), and rubella (1969), and was routinely given when toddlers were about 15 months old
  • routine vaccination with smallpox vaccines end in the US in 1972

The Vaccination Era

The end of the 20th century brought more vaccines and protection against even more now vaccine preventable diseases.

  • Pneumovax, the first pneumococcal vaccine that protects kids and adults from certain types of Streptococcus pneumoniae bacteria is approved in 1971 and is given to high-risk kids
  • President Jimmy Carter’s  National Childhood Immunization Initiative in 1977 reached its goal of immunizing 90% of children
  • the Thirty-Third World Health Assembly declares that smallpox is eradicated in 1979
  • Menomune, the first meningococcal vaccine is licensed in 1981 and is recommended for high-risk kids until it is later replaced by Menactra
  • a plasma-derived hepatitis B vaccine is licensed in 1981
  • Vaccine Roulette, a controversial news segment, airs in 1982 and attempts to associate the DPT vaccine with permanent brain damage, downplays the risks of pertussis disease and helps start much of the modern American anti-vaccine movement
  • a Haemophilus b capsular polysaccharide vaccine is licensed in 1985, but unfortunately does not provide good protection in kids younger than 18 to 24 months, who are most at risk for Haemophilus influenzae Type b disease
  • a recombinant hepatitis B vaccine (Recombivax HB) is approved in 1986 but is only recommended to be used in those at high risk for infection
  • another hepatitis B vaccine, Engerix-B, is approved in 1989
  • the first Haemophilus b conjugate vaccine (PRP-D) is approved in 1988 to provide protection against Haemophilus influenzae type b disease in all kids at least 18 months old, but in 1990, they are replaced with two improved Hib conjugate vaccines (PRP-HbOC and PRP-OMP) that can be given to infants as young as two months old
  • a booster dose of MMR is first recommended in 1989, but only for kids who live in counties that have at least 5 cases of measles. The routine 2 dose MMR schedule wasn’t put into use for all kids until 1994.
  • the Vaccine Adverse Events Reporting System (VAERS) is established in 1990
  • the hepatitis B and Hib vaccines are recommended for all infants in 1991
  • after year’s of neglect under President Reagan, President George HW Bush’s immunization action plan in 1991 once again raised immunization rates following three years of measles outbreaks
  • the DTaP vaccine, which is supposed to have fewer side effects than DTP is licensed, and by 1997 replaces DTP for all required doses, although DTP is never actually shown to have caused seizures or brain damage, as was once claimed in Vaccine Roulette
  • President Bill Clinton’s Childhood Immunization Initiative in 1993 includes signing the Vaccines for Children (VFC) Act, providing free vaccines to many children
  • the WHO declares that polio has been eliminated from the Western Hemisphere in 1994
  • a vaccine to protect kids against chicken pox (Varivax) is licensed in 1995
  • VAQTA, the first hepatitis A vaccine is approved by the FDA in 1996 for kids who are at least two years old, but is mainly given to kids at high risk to get hepatitis A
  • the Salk inactivated polio vaccine (IPV) is once again recommended for kids and replaces the oral polio vaccine (OPV) in 1996 because of a small risk of vaccine-associated paralytic poliomyelitis (VAPP), beginning with a sequential IPV-OPV vaccine schedule and then going to an all IPV schedule in 2000
  • RotaShield, the first rotavirus vaccine is licensed in 1998 but is soon withdrawn from the market in 1999 after it is associated with an increased risk of intussusception, a form of bowel obstruction
  • LYMErix, a Lyme disease vaccine, is licensed in 1998
  • Dr. Andrew Wakefield publishes a report in the journal Lancet and attempts to link the MMR vaccine to autism
  • thimerosal is removed from the vast majority of vaccines in the childhood immunization schedule in 1999 and 2000
  • endemic measles is declared eliminated in the United States in 2000
  • Prevnar, a newer pneumococcal vaccine is licensed in 2000 and is added to the immunization schedule the next year
  • LYMErix goes off the market because of insufficient sales in 2002
  • Flumist, a live, intranasal flu vaccine, is approved in 2004
  • endemic rubella is declared eliminated in the United States in 2004
  • a flu shot for all healthy children between 6 and 23 months became a formal recommendation for the 2004-05 flu season.
  • beginning in the 2004-05 flu season, a flu shot is recommended for women who will be pregnant during flu season, in any trimester, which is different than previous recommendations for a flu vaccine if a women was going to be beyond the first trimester of pregnancy during flu season. Unfortunately, even though they are in a high-risk category, only about only 13% of pregnant women received a flu vaccine in 2003.
  • Havrix, another hepatitis A vaccine, is approved in 2005 and the age indication for both hepatitis A vaccines is lowered to 12 months.
  • Menactra, a vaccine to protect against certain types of meningococcal disease is licensed in 2005 and is added to the immunization schedule in 2006, being recommended for all at 11 to 12 years of age or when they enter high school
  • the Tdap vaccine (Boostrix or Adacel) is recommended for teens and adults to protect them from pertussis in 2006 and replaces the previous Td vaccine that only worked against tetanus and diphtheria
  • RotaTeq, another rotavirus vaccine, is licensed in 2006, and is added to the immunization schedule in 2007
  • the hepatitis A vaccine is added to the routine childhood immunization schedule in 2006
  • Gardasil, the first HPV vaccine, is approved in 2006
  • a shingles vaccine, Zostavax, is approved for adults in 2006
  • a 2nd booster dose of the chicken pox vaccine is added to the immunization schedule in 2007 to help prevent breakthrough infections

The Post Vaccination Era

Why call it the post-vaccination era?

It has been some time since a vaccine for a new disease has been added to the routine vaccination schedule, but we are also starting to see more and more outbreaks of old diseases, especially pertussis, mumps, and measles.

  • another rotavirus vaccine, RotaRix, is approved in 2008
  • another HPV vaccine, Cervarix, is approved in 2009
  • another meningococcal vaccine, Menveo, is approved in 2010
  • a newer version of Prevnar, which can provide coverage against 13 strains of the pneumococcal bacteria, is approved and replaces the older version (Prevnar 7) in 2010
  • Fluzone Intradermal and Fluzone High-Dose are two new flu vaccine options that became available in 2011
  • a combination vaccine that protects against both Haemophilus influenzae type b and Neisseria meningitidis serogroups C and Y was approved by the FDA in 2013. MenHibrix is recommended for infants at high risk for meningococcal disease.
  • Quadrivalent flu vaccines, which protect against four strains of flu, become available for the 2013-14 flu season
  • Trumenba, the first vaccine to protect against serogroup B Meningococcal disease is approved by the FDA (October 2014). Previously, Bexsero, a MenB vaccine that is approved in some other countries, was given to some college students during outbreaks under the FDA’s expanded access program for investigational products. Both are now recommended by the ACIP for those at increased risk for meningococcal serogroup B infections.
  • Gardasil 9 is approved by the FDA (December 2014) to provide protection against five additional types of HPV.
  • Cervarix is discontinued in the US in 2016 because of poor sales
  • Vaxchora is approved to in 2016 for adults traveling to cholera-affected areas

More Information About Vaccine Timelines

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Discontinued Vaccines

tripedia
The Tripedia DTaP vaccine was discontinued in 2013.

Most people know that the RotaShield rotavirus vaccine was discontinued in 1999 because it was found to be linked to intussusception.

It took eight years for a new rotavirus vaccine to be licensed.

Lymerix, a Lyme disease vaccine was discontinued in 2002. Unfortunately, we still don’t have a new replacement Lyme disease vaccine.

Vaccines That Have Been Discontinued

More commonly, a vaccine gets discontinued with little notice, as there are other options to keep kids vaccinated and protected.

Other vaccines that are no longer made, include:

  • Cervarix – an HPV vaccine that was discontinued in the US in 2016
  • Comvax –  a Hib/Hepatitis B combination – discontinued in 2014
  • Tetanus toxoid – discontinued 2013
  • Tripedia – a DTaP vaccine – discontinued 2011
  • TriHIBit – a DTaP/Hib combination
  • JE-VAX – discontinued 2005
  • Attenuvax – measles vaccine
  • Mumpsvax – mumps vaccine
  • Meruvax II – rubella vaccine
  • M-R-Vax – measles and rubella combo
  • M-M-Vax – measles and mumps combo
  • Biavax II – rubella and mumps combo
  • Heptavax-B – the original hepatitis B vaccine
  • HIB-Vax – the original Hib vaccine
  • Plague vaccine
  • Poliovax
  • Dryvax – smallpox vaccine
  • Measles-Smallpox combination vaccine
  • Diptussis – a diphtheria/pertussis combination (1949-55)
  • Quadrigen – a DTP/Polio combination (1959-68)
  • Streptococcus vaccine (1952-88)
  • Serobacterin – a pertussis vaccine (1945-54)
  • Rocky mountain spotted fever vaccine (1942-78)
  • Typhus vaccine (1941-79)
  • smallpox vaccine (1917-1976)

Most of these vaccines were discontinued because they simply became obsolete.

Orig. Title: SPvac806.8a
A smallpox vaccination kit included the diluent, a vial of Dryvax smallpox vaccine, and a bifurcated needle.

The Hib-Vax and Heptavax-B vaccines, for example, both use older technology, so these vaccines were discontinued when newer Hib and hepatitis B vaccines were introduced.

And some vaccines are discontinued  or are phased out when they get an update:

  • MMR -> MMR-II (1978)
  • Prevnar 7 -> Prevnar 13 (2010)
  • Gardasil -> Gardasil 9 (2014)

Still other vaccines, like Tripedia and TriHIBit, seemed to get discontinued as a business decision. Through mergers, Sanofi Pasteur, Ltd. ended up with two DTaP vaccines. They had their own Daptacel, but also had Tripedia, a vaccine they acquired from Pasteur Merieux. They ended up discontinuing Tripedia.

Merck also stopped making Comvax not because of “any  product safety or manufacturing issues,” but rather “as part of its ongoing effort to focus company resources on opportunities that provide the greatest value for customers, patients, and public health…”

Cervarix was discontinued because of low market demand. The competing HPV vaccine, Gardasil, had the much larger market share.

Vaccine Manufacturers and Discontinued Vaccines

And of course, some vaccine manufacturers simply stopped making vaccines.

The Texas Department of Health Resources once had a license to make vaccines, including DTP, diphtheria, DT, pertussis, tetanus, Td, and typhoid vaccines since 1950. They completely exited the vaccine market in 1979.

In the 1970s and 80s, dozens of vaccines were discontinued as Miles Inc., Eli Lilly, Parke Davis, and other companies stopped making vaccines.

While that is often downplayed these days, it is important to realize that we used to have much more competition among vaccine manufacturers. For example, in the early 1970s, the DTP vaccine was made by at least 11 different companies! We now have just two that make DTaP. And in many other cases, like for Prevnar, MMR-II, polio, and the chicken pox vaccine, there is just one manufacturer.

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Polio Pioneers

The Polio Pioneers have been described as “the largest clinical trial in history.”

It was led by Thomas Francis Jr.

The blinded trial involved 1.3 million children in elementary school, grades 1 to 3, who either got Salk‘s inactivated polio shot, a saline placebo, or were observed control subjects.

Randall Kerr is said to be the first Polio Pioneer, getting a polio shot (or a placebo), at Franklin Sherman Elementary School in Fairfax, Virginia on April 26, 1954.

Children lined up for their shots in 44 states, with very few failing to get all three shots over the course of the trial, which continued until July 10, 1954.Upon getting their third shot, kids got a Polio Pioneers button and card, which many still have today.

The results of the trial, that Salk’s vaccine work, was reported on April 12, 1955.

How did people react to the news?

salk-trial
The success of the Polio Pioneers trial made front headlines in major newspapers.

It is said the Salk’s mother wept when she heard the news.

Mrs. Roosevelt, who was observing the ten year anniversary of FDR’s death, said that she was “delighted” about the success of the Polio Pioneers trial.

Routine vaccination with the Salk polio vaccine began soon after, on April 25, 1955.

Polio Pioneer Reunions

Although more than a few Polio Pioneers have gone online to coment on their experiences, in 2003, Ben Wechsler got the idea for a big reunion.

A former Polio Pioneer who had become the director of the Pittsburgh East Rotary Club (a club that works to end polio around the world), he found a box of microfilm that Dr. Thomas Francis had left to the medical history library at the University of Michigan and found the names of all of the original Polio Pioneers.

He then set out to find them…

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Jonas Salk

Dr. Jonas Salk developed the first polio vaccine in 1955, just before Albert Sabin developed his oral polio vaccine in 1961.

Approval of Salk’s vaccine followed national testing of the Polio Pioneers, one million children between the ages of six to nine years. Salk also gave his experimental vaccine to his children, his wife, and of course, to himself.

In 1955, he appeared on See It Now and told Edward R. Murrow:

Who owns the patent on this vaccine?
Well, the people, I would say. There is no patent. Could you patent the sun?

Although he could not have patented his vaccine if he had wanted to, he was right that “there is no patent.” The National Foundation for Infantile Paralysis, which he was working for, didn’t patent the vaccine either.

In 1961, Sabin’s live, attenuated polio vaccine replaced Jonas Salk’s inactivated polio vaccine that had been in use since 1955. The United States switched back to IPV in 2000 because of concerns over VAPP.

In addition to his vaccine, his Salk Institute for Biological Studies continues to do research on aging and regenerative medicine, cancer biology, immune system biology, metabolism and diabetes, neuroscience and neurological disorders and plant biology.

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Gregory A. Poland on Vaccines

Gregory Poland, MD is well known for many things that he has done in his long career as a pediatric infectious disease specialist and vaccinologist, including receiving the Charles Merieux Lifetime Achievement Award in Vaccinology from the National Foundation for Infectious Diseases in May 2006.

He has published over 350 peer-reviewed scientific journal articles and chapters in books and he is the Editor-in-Chief for the journal Vaccine.

As Director of Mayo Clinic’s Vaccine Research Group, Dr. Poland has a focus on “vaccinomics,” or the “development of personalized vaccines based on the increased understanding of immune response phenotype-genotype information,” working “to explain how vaccine-induced immune responses and vaccine-related adverse events may be genetically determined — and therefore predictable.”

He is sometimes known for being misquoted by anti-vaccine groups, who use his words out of context, sometimes even in testimony against state vaccine laws, because of his article highlighting some of the limitations of the measles vaccine.

Some pediatricians and vaccine hesitant parents may also know Dr. Poland for these quotes:

The way forward is clear. Because no credible evidence during the past 13 years supports the hypothesized connection between the MMR vaccine and autism disorders, it is bereft of credible evidence and must be discarded.

To continue pouring money into futile attempts to prove a connection to the MMR vaccine when multiple high-quality scientific studies across multiple countries and across many years have failed to show any hint of a connection, and in the face of biologic nonplausibility, is dangerous and reckless of lives, public funding, and ultimately public health.

At some point, a point I believe we have well passed, the small group of people who claim such connections, who have no new or credible data, and for which their assumptions and hypotheses have been discredited must simply be ignored by scientists and the public and, most importantly, by the media, no matter how passionate their beliefs to the contrary.

At this point, the antivaccine groups and conspiracy proponents promoting such an association should be ignored, much as thinking people simply ignore those who continue to insist that the earth is flat or that the US moon landing in 1969 did not really occur.

There is no law against being foolish, nor any vaccine against ignorance; however, in the meantime the health of millions of children in the United States and worldwide is being placed at unnecessary and real risk through continued deliberate misinformation and discredited unscientific beliefs, and that should be a crime.

Having given us all clear advice on how to deal with “antivaccine groups and conspiracy proponents,” hopefully he can now focus on vaccinology and vaccinomics.

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Efficacy vs Effectiveness of Vaccines

According to the CDC:

Vaccine efficacy and vaccine effectiveness measure the proportionate reduction in cases among vaccinated persons.

But what’s the difference between vaccine efficacy and effectiveness?

Vaccine efficacy is used when a study is carried out under ideal conditions, for example, during a clinical trial.

Vaccine effectiveness is used when a study is carried out under typical field (that is, less than perfectly controlled) conditions.

Postlicensure studies can often help figure out vaccine effectiveness. For example, the study “Varicella Vaccine Effectiveness in the US Vaccination Program: A Review,” that appeared in The Journal of Infectious Diseases in 2008 “reviewed the results of postlicensure studies of varicella vaccine effectiveness and compared these results with those of prelicensure efficacy trials.”

That study of the chicken pox vaccine found that “the estimates of effectiveness are lower than the prelicensure efficacy,” although several studies found the vaccine “100% effective in preventing combined moderate and severe varicella.”

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