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17.1H: Production of Vaccines, Antibiotics, and Hormones - Biology

17.1H: Production of Vaccines, Antibiotics, and Hormones - Biology


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Biotechnological advances in gene manipulation techniques have further resulted in the production of vaccines, antibiotics, and hormones.

Learning Objectives

  • Discuss the methods by which biotechnology is used to produce vaccines, antibiotics, and hormones.

Key Points

  • Vaccines use weakened or inactive forms of microorganisms to mount the initial immune response through the use of antigens, which are produced through use the genes of microbes that are cloned into vectors.
  • Antibiotics, agents that inhibit bacterial growth or kill bacteria, are produced by cultivating and manipulating fungal cells.
  • Hormones, such as the human growth hormone (HGH), can be formulated through recombinant DNA technology; for example, HGH can be cloned from a cDNA library and inserted into E. coli cells by cloning it into a bacterial vector.

Key Terms

  • bactericidal: that which kills bacteria
  • bacteriostatic: that which slows down or stalls bacterial growth
  • antigen: a substance that binds to a specific antibody; may cause an immune response

Production of Vaccines, Antibiotics, and Hormones

Vaccines

Traditional vaccination strategies use weakened or inactive forms of microorganisms to mount the initial immune response. Modern techniques use the genes of microorganisms cloned into vectors to mass produce the desired antigen. The antigen is then introduced into the body to stimulate the primary immune response and trigger immune memory. Genes cloned from the influenza virus have been used to combat the constantly-changing strains of this virus.

Antibiotics

Antibiotics are biotechnological products that inhibit bacterial growth or kill bacteria. They are naturally produced by microorganisms, such as fungi, to attain an advantage over bacterial populations. Antibiotics are produced on a large scale by cultivating and manipulating fungal cells. Many antibacterial compounds are classified on the basis of their chemical or biosynthetic origin into natural, semisynthetic, and synthetic. Another classification system is based on biological activity. In this classification, antibiotics are divided into two broad groups according to their biological effect on microorganisms: bactericidal agents kill bacteria, and bacteriostatic agents slow down or stall bacterial growth.

Hormones

Recombinant DNA technology was used to produce large-scale quantities of human insulin (a hormone) in E. coli as early as 1978. Previously, it was only possible to treat diabetes with pig insulin, which caused allergic reactions in humans because of differences in the gene product. In recent times, human growth hormone (HGH) has been used to treat growth disorders in children. The HGH gene was cloned from a cDNA library and inserted into E. coli cells by cloning it into a bacterial vector. The bacteria was then grown and the hormone isolated, enabling large scale commercial production.


Genetic engineering applied to the development of vaccines

The simplest application of the modern genetic manipulation methods to vaccine development is the expression in microbial cells of genes from pathogens that encode surface antigens capable of inducing neutralizing antibodies in the host of the pathogen involved. This procedure has been exploited successfully for development of a vaccine against hepatitis B virus (HBV) that is now widely used. Similar approaches have been directed towards formulations for immunization against several other animal and human diseases and some of these preparations are now presently in trials. Of no less importance is the impact of biotechnology in providing reagents for fundamental studies of topics such as the determination of virulence, antigenic variation, virus receptors and the immunological response to viral antigens. The core antigen of HBV is a good example of a product of genetic engineering that is a valuable diagnostic reagent, and that is finding important use in immunological studies of particular pertinence to vaccine development.


What are flu vaccines made of and why?

Flu shots contain various ingredients that together ensure that the vaccine is safe and effective. The specific ingredients vary slightly among vaccines.

The viruses that cause the flu, known as influenza viruses, are constantly changing. To ensure the flu vaccine remains effective, researchers and manufacturers work together to update the vaccine every year.

The Centers for Disease Control and Prevention (CDC) recommend that everyone 6 months of age and older, with a few exceptions, have a flu vaccine every year.

The CDC confirm that getting the vaccine is the best way to avoid getting the flu and spreading it to other people.

Different flu vaccines have slightly different ingredients. For instance, the vaccine may be:

  • An injection: In this case, it usually contains tiny amounts of deactivated, and therefore not harmful, flu viruses.
  • A nasal spray: In this case, it contains live viruses that have been weakened, and are therefore not harmful. Nasal spray vaccines are approved for people aged 2–49 only.

In light of the ongoing COVID-19 pandemic, reducing the spread of respiratory illnesses, including the flu, is more important than ever.

This article looks at the various ingredients that flu shots contain, their function, and the safety of the vaccines.

Share on Pinterest Image credit: lechatnoir/Getty Images

Many vaccines for the flu and other viral infections contain similar ingredients. The purpose of each ingredient is either to make the vaccine effective or ensure that it is safe.

Many studies over the years have shown that flu vaccines are safe and effective, reducing flu cases and related hospitalizations.

Below, learn about seven ingredients in flu shots and the function of each:

Influenza viruses

Flu vaccines contain tiny amounts of the viruses that the vaccine protects against.

In the shot, these viruses are inactivated, or dead, so they cannot cause the flu. The nasal spray contains live viruses, but they are weakened, or attenuated, so that they, too, cannot cause the flu.

The presence of these inactive viruses triggers the body’s natural defense mechanism — the immune system — which produces antibodies to fight these viruses.

The body remembers, or stores, their appearance, so that it can quickly recognize any live versions of these viruses and create antibodies to fight them as well.

Traditional flu shots are trivalent, or three-component, vaccines. This means that they protect against three viruses: two influenza A viruses, H1N1 and H3N2, and one influenza B virus.

The specific viruses in an annual shot depend on which are likely to circulate during that year’s flu season. Researchers make this prediction.

The influenza viruses contained in the trivalent 2020–2021 flu vaccine are:

  • the influenza A virus H1N1, also known as the Guangdong-Maonan strain
  • the influenza A virus H3N2, also known as the Hong Kong strain
  • an influenza B virus known as the Washington strain

A person can also get a quadrivalent, or four-component, vaccine that protects against an additional influenza B virus. In 2020–2021, this is one known as the Phuket strain.

Formaldehyde

Formaldehyde, a chemical typically present in the human body, is a product of healthy digestive function.

In high doses, formaldehyde is toxic and potentially lethal. However, the tiny amounts present in flu vaccines are harmless .

Formaldehyde’s role in a flu shot is to inactivate toxins from viruses and bacteria that may contaminate the vaccine during production.

Aluminum salts

Aluminum salts are adjuvants — they help the body develop a stronger immune response against the virus in the vaccine. This allows scientists to include smaller amounts of the inactivated influenza viruses in these vaccines.

As with formaldehyde and most ingredients in flu shots, the amount of aluminum present is extremely small.

Aluminum salts are also in drinking water and various health products, such as antacids and antiperspirants. They are not always present in flu vaccines, some of which are aluminum-free.

Thimerosal

Thimerosal is a preservative, and it keeps vaccines from becoming contaminated.

This ingredient is only present in multi-dose vials, which contain more than one dose. Without it, the growth of bacteria and fungi are common in these vials.

Single-dose vials, prefilled syringes, and nasal sprays do not need a preservative, because the risk of contamination is so low.

Thimerosal has been safely included in vaccines since the 1930s. It comes from an organic form of mercury called ethylmercury, a safe compound that — unlike other forms of mercury — does not remain in the body.

Ethylmercury is different from the standard form of mercury that can cause illness in large doses, and it is also different from the mercury found in seafood, called methylmercury, which can stay in the body for years.

Chicken egg proteins

These proteins help the viruses grow before they go into the vaccine.

The inactivated influenza viruses present in vaccines are usually grown inside fertilized chicken eggs, where the virus replicates. Then, the manufacturers separate the virus from the egg and include it in the vaccine.

As a result, the finished vaccine may contain small amounts of egg proteins.

The CDC say that people with egg allergies can receive the standard flu vaccine, but that those severe allergies should do so in a supervised medical setting.

Egg-free flu shots are also available.

Gelatin

Gelatin is present in the flu shot as a stabilizer — it keeps the vaccine effective from the point of production to the moment of use.

Stabilizers also help protect the vaccine from the damaging effects of heat or freeze-drying.

Most flu vaccines use pork-based gelatin as a stabilizer.

Antibiotics

Antibiotics in flu vaccines keep bacteria from growing during the production and storage of the products.

Vaccines do not contain antibiotics that can cause severe reactions, such as penicillin. Instead, they contain other forms, such as gentamicin or neomycin, which is also an ingredient in many topical medications, such as lotions, ointments, and eye drops.

Receiving a flu vaccine has several benefits , including:

  • Preventing the person and those around them from developing the flu.
  • Reducing the risk of hospitalization, particularly among children and older adults.
  • Protecting vulnerable groups, including babies, older people, and people with chronic diseases.
  • Protecting people during and after pregnancy by reducing both the risk of flu-associated acute respiratory infections and the likelihood of the infant getting the flu.
  • Preventing complications in people with chronic diseases.

As an example of the last point: The vaccine decreases the rate of major heart problems in people with heart disease. It also reduces the rate of hospitalizations in people with chronic lung disease and diabetes.

The CDC recommend that everyone 6 months and older receive the flu vaccine every year, though they also provide guidelines about who should either avoid the vaccine or take extra precautions.

Age, current and past health status, and allergies to any ingredients in the flu vaccine are factors to consider.

The following groups should not receive the flu vaccine or may require additional precautions:

  • infants under 6 months of age
  • people with severe allergies to any of the ingredients, such as gelatin or eggs
  • anyone who has had a severe allergic reaction to a previous flu shot
  • people who have had Guillain-Barré syndrome
  • people who are not feeling completely healthy

The flu vaccine cannot cause the flu because it contains either inactivated or weakened viruses that are no longer infectious or synthetic, lab-made variants. Learn more here.

A flu shot may cause slight flu-like symptoms, however. These usually appear soon after the shot and last 1–2 days . They can include:

The most common side effect is a slight soreness or redness in the arm, at the site of the injection.

In rare circumstances, the flu vaccine can cause serious side effects, such as allergic reactions. These usually occur within a few minutes to hours after vaccination, and they are treatable.

Many myths about vaccinations circulate — including that they weaken the immune system, cause autism, or contain unsafe toxins. These claims are not based on scientific evidence.

Flu shots contain various ingredients that work together to ensure that the vaccine is safe and effective. The specific ingredients vary slightly among vaccines.

Ingredients often include deactivated influenza viruses, chemicals that boost the body’s response to the vaccine, preservatives to prevent contamination, and stabilizers.

The CDC recommend getting a flu shot in September or October, but getting one any time during flu season will help.

How and where people receive their flu shots may vary due to the COVID-19 pandemic. The CDC provide more information about finding a shot here .


What ingredients are in vaccines?

Vaccines are a central player in our fight against infectious diseases. What components are commonly found in vaccines, and what is their purpose? In this Special Feature article, we find out.

Share on Pinterest Why do some vaccines have a long list of components?

Many people will be familiar with the concept that a vaccine against a particular virus will contain a small amount of the pathogen or a part of it, at least.

When we receive the vaccine, the viral interloper triggers our immune system to launch a series of events that leave us protected against the pathogen in the future.

But a glance at the ingredients in common vaccines reveals a long list of other components, the roles of which might not seem so clear cut.

What is the purpose of the likes of gelatin, thimerosal, and Polysorbate 80? And why do some vaccines contain aluminum?

In this Special Feature article, we look at the active and inactive ingredients that make their way into vaccines and reveal what their role is in protecting us from infectious diseases.

The active ingredient in a vaccine is usually made from the viral or bacterial pathogen itself. There are two different approaches to this, with the pathogen being either alive or inactivated.

Vaccines that incorporate living bacteria or viruses are called live attenuated vaccines. The pathogen is weakened to prevent it from causing the disease, but it is still able to elicit a strong immune response.

Live attenuated vaccines work very well, but they are not suitable for everyone. If a person is immunocompromised, they may contract the very disease from which the vaccine should be protecting them.

Many vaccines, therefore, use an inactivated version of the active ingredients, which can take the form of whole bacteria or viruses that have been killed.

However, most vaccines are actually acellular, which means that they do not contain the whole pathogenic organism. Instead, they are made from parts of the pathogen, such as proteins or sugar molecules. Our bodies recognize these molecules as foreign and mount an immune response.

Examples of acellular vaccines are:

  • toxoid vaccines that contain inactivated toxins from pathogenic bacteria
  • conjugate vaccines made from a combination of pathogen-specific sugar molecules and toxoid proteins, as the sugars themselves do not cause sufficiently strong immune responses
  • recombinant vaccines made by using bacteria or yeast cells to make many copies of specific molecules from the pathogen

Aside from the active ingredient, vaccines contain many other things. The technical term for these is excipients.

Excipients include preservatives and stabilizers, traces of things that were used to produce the vaccine, and adjuvants.

Although many vaccines contain active ingredients that are strong enough to kick our immune system into gear, some need a little bit of extra help to be effective.

Adjuvants are compounds that elicit a strong immune response, improving how well a vaccine works.

Examples of adjuvants include:

  • metals
  • oils
  • biological molecules, such as components isolated from bacteria and synthetic DNA

Aluminum , in the form of aluminum salt, features in a variety of vaccines, including several routine childhood vaccines. Scientists believe that this adjuvant increases the production of antibodies.

Aluminum is a naturally occurring metal that has many uses aside from its adjuvant properties. Cans, foil, and some window frames contain aluminum.

Aluminum salts are also used in the food industry as additives.

As an adjuvant, aluminum has a long history going back to the 1930s . Despite its widespread use, some scientists believe that the metal can cause damage to the nervous system and promote autoimmunity.

However, many experts disagree with this assessment, pointing out that some of the research implicating aluminum has been retracted .

The Food and Drug Administration (FDA) published a study in 2011 in the journal Vaccine , which concluded that “episodic exposures to vaccines that contain aluminum adjuvant continue to be extremely low risk to infants and that the benefits of using vaccines containing aluminum adjuvant outweigh any theoretical concerns.”

Another example of an adjuvant is squalene , a naturally occurring oil.

The Fluad vaccine, a flu vaccine licensed for adults aged 65 years and older, contains an adjuvant called MF59, which is an oil-in-water emulsion containing squalene. The squalene used in MF59 is purified from shark liver oil.

In 2000, a research team pointed to a link between squalene and Gulf War Syndrome, prompting fears about the safety of this adjuvant.

However, subsequent research did not back up the findings, and the World Health Organization (WHO) concluded in 2006 that these fears were “unfounded.”


Certain antibiotics may be used in some vaccine production to help prevent bacterial contamination during manufacturing. As a result, small amounts of antibiotics may be present in some vaccines. Because some antibiotics can cause severe allergic reactions in those children allergic to them (such as hives, swelling at the back of the throat, and low blood pressure), some parents are concerned that antibiotics contained in vaccines might be harmful. However, antibiotics most likely to cause severe allergic reactions (e.g., penicillins, cephalosporins and sulfa drugs) are not used in vaccine production, and therefore are not contained in vaccines.

Examples of antibiotics used during vaccine manufacture include neomycin, polymyxin B, streptomycin and gentamicin. Some antibiotics used in vaccine production are present in the vaccine, either in very small amounts or they are undetectable. For example, antibiotics are used in some production methods for making inactivated influenza virus vaccines. They are used to reduce bacterial growth in eggs during processing steps, because eggs are not sterile products. The antibiotics that are used are reduced to very small or undetectable amounts during subsequent purification steps. The very small amounts of antibiotics contained in vaccines have not been clearly associated with severe allergic reactions.


Growing the active ingredients

Human Cell Lines

For some vaccines, the active ingredient is grown in laboratories on cultures that contain human cells. Some viruses, such as chickenpox (varicella), grow much better in human cells. After they are grown, the viruses are purified several times to remove the cell culture material. This makes it unlikely that any human material remains in the final vaccine.

For vaccines used in the UK, human cell lines are used to grow viruses for these vaccines:

  • the rubella part of both MMR vaccines (MMRVaxPro and Priorix)
  • the shingles vaccine (Zostavax)
  • both chickenpox vaccines (Varivax and Varilrix)

The cell lines currently used (called WI-38 and MRC-5) were started in the 1960s using lung cells taken from two aborted foetuses. The abortions were legal and agreed to by the mothers, but they were not performed for the purpose of vaccine development.

Some people may have moral concerns about using a vaccine produced in this way. In 2005 the Vatican’s Pontifical Academy for Life issued a statement called ‘Moral reflections on vaccines prepared from cells derived from aborted human foetuses’. This statement says that they believe it is wrong to make vaccines using human cell strains derived from foetuses, and that there is a ‘moral duty to continue to fight’ against the use of such vaccines and to campaign for alternatives. However, it also states that if the population is exposed to ‘considerable dangers to their health’ through diseases such as rubella (German measles), then ‘vaccines with moral problems pertaining to them may also be used on a temporary basis’.

HEK-293 cell line

The manufacturing process for the Oxford-AstraZeneca vaccine involves the production of a virus, the adenovirus, which carries the genetic material to the cells inside the body. To produce this virus in the laboratory, a “host” cell line is needed. The Oxford-AstraZeneca vaccine uses a cell line called HEK-293 cells.

HEK-293 is the name given to a specific line of cells used in various scientific applications. The original cells were taken from the kidney of a legally aborted foetus in 1973. HEK-293 cells used nowadays are clones of those original cells, but are not themselves the cells of aborted babies.

The Department for Social Justice of the Catholic Bishops’ Conference of England and Wales released a statement addressing the use of HEK-293 cells in the COVID-19 vaccine. They say that “one may in good conscience and for a grave reason receive a vaccine sourced in this way”, and “that one does not sin by receiving the vaccine”.

Other therapeutic products which use HEK-293 cells as a producer cell line include Ad5 based vaccines, such as Cansino’s COVID-19 vaccine, Adeno associated viruses (AAV) and lentiviruses as gene therapy vectors for various diseases. Many of these products are in clinical trials.

Animal Cell Lines

Viruses for some vaccines are grown in laboratories using animal cell cultures. This is because viruses will only grow in human or animal cells. In the UK schedule this applies to these vaccines:

  • The polio part of the 6-in-1 vaccine (Infanrix Hexa), the pre-school booster vaccines (Repevax, Infanrix IPV and Boostrix-IPV) and the teenage booster vaccine (Revaxis)
  • The Rotavirus vaccine (Rotarix)
  • One of the Inactivated flu vaccines (QIVc)

Viruses for these vaccines are grown on Vero cells. This is a cell line started in the 1960s using kidney cells from an African green monkey.

The measles and mumps parts of the MMR vaccines (MMRVaxPro and Priorix) are grown on a culture which began with cells taken from a chick embryo.

There is no evidence of any risk that animal diseases can be transmitted by vaccines grown on animal cell lines.

Genetically Modified Organisms (GMOs)

The only vaccine in the UK schedule which contains GMOs is the Nasal Flu vaccine (Fluenz). The viruses for flu vaccines are usually made by injecting two flu virus strains into an egg and letting them recombine naturally to make new strains. Researchers then look through all the new viruses to see which one has the features they are looking for to make this year’s vaccine. The viruses used to make Fluenz are custom-made by putting together individual genes that will give the right features. This is a quicker and more accurate process.

The Oxford-AstraZeneca vaccine for COVID-19, ChAdOx1 nCoV-19, is made using a modified adenovirus, which is used to carry the genetic code for the coronavirus spike protein. This means that the vaccine is a GMO. The adenovirus has been modified in this way to prevent it from replicating inside the body so that it cannot cause an infection.

Recombinant DNA Technology

Recombinant vaccines are made using bacterial or yeast cells to manufacture the vaccine. A small piece of DNA is taken from the virus or bacterium that we want to protect against. This is inserted into other cells to make them produce large quantities of active ingredient for the vaccine (usually just a single protein or sugar).

For example, to make the hepatitis B vaccine, part of the DNA from the hepatitis B virus is inserted into the DNA of yeast cells. These yeast cells are then able to produce one of the surface proteins from the hepatitis B virus, and this is purified and used as the active ingredient in the vaccine. Proteins for the HPV vaccine, part of the MenB vaccine and the hepatitis B part of the 6-in-1 vaccine are produced using a similar technique.

Bovine products

‘Bovine products’ refers to any product that is derived from a cow or calf (such as bovine serum, which comes from cow's blood). Some sources state that bovine products may be present in the media that are used to grow the viruses or bacteria that are used to make the components of some vaccines. The Vaccine Knowledge Project has only been able to find one vaccine currently used in the UK which states that bovine products are used in its manufacture. This is Repevax, one of the Pre-school Booster vaccines available in the UK. The Summary of Product Characteristics sheets (SPC) for Repevax states that bovine serum albumin is used in the manufacture of the vaccine and that trace amounts may remain in the vaccine. This is potentially a risk for people who are severely allergic to bovine products. Other vaccines in use in the UK may use bovine products in their manufacture, but this is not stated on their SPCs.

The European Medicines Agency (EMA) has issued a series of statements and Q&A sheets on the risk posed by bovine products used in vaccine manufacture . These have been prepared in response to the recognition of BSE in the 1980s and are regularly updated.

Other growing media

Some bacteria do not need to be grown on human or animal cells. Instead they can be grown on cultures that are rich in proteins, vitamins and salts. Cultures that are often used in the production of vaccines are Medium 199, Eagle Medium and Minimum Essential Medium.


Global Pediatric Drugs and Vaccines Industry

LONDON , July 19, 2017 /PRNewswire/ -- This report analyzes the worldwide markets for Pediatric Drugs and Vaccines in US$ Million by the following Therapeutic Class: Pediatric Vaccines, Pediatric Hormones, Allergy & Respiratory Drugs, Anti-infective Drugs, CNS Drugs, and Other Pediatric Drugs. The Pediatric Vaccines market is also analyzed by the following Types: Combinations, Hepatitis, MMR, Varicella, Poliovirus, Pneumococcal, and Others.

The report provides separatecomprehensive analytics for the US, Canada , Japan , Europe , Asia-Pacific , Latin America , and Rest of World. Annual estimates and forecasts are provided for the period 2016 through 2024.

Also, a five-year historic analysis is provided for these markets. Market data and analytics are derived from primary and secondary research. Company profiles are primarily based on public domain information including company URLs.

The report profiles 90 companies including many key and niche players such as
- Abbott Laboratories
- Allergan, Inc.
- Amgen, Inc.
- AstraZeneca Plc
- Boehringer Ingelheim GmbH

PEDIATRIC DRUGS AND VACCINES MCP-6503 A GLOBAL STRATEGIC BUSINESS REPORT CONTENTS

I. INTRODUCTION, METHODOLOGY & PRODUCT DEFINITIONS
Study Reliability and Reporting Limitations
Disclaimers
Data Interpretation & Reporting Level
Quantitative Techniques & Analytics
Product Definitions and Scope of Study

1. INDUSTRY OVERVIEW
Pediatrics: A Highly Underserved and Undervalued Group
Table 1: Global New Births (in Millions) per Annum by Geographic Region (includes corresponding Graph/Chart)
Table 2: Global Birth Rates: Number of Births (per '000 Population) for the Years 1990, 1995, 2000, 2005, 2010, and 2015 (includes corresponding Graph/Chart)
Table 3: Top 25 Countries in Global Birth Rates Worldwide (2014): Ranked by Number of Births per 1000 Population (includes corresponding Graph/Chart)
Table 4: Top 25 Countries in terms of Fertility Rates Worldwide (2014) - Ranked by Number of Children Born Per Woman (includes corresponding Graph/Chart)
Pediatric Drugs Market - An Abode of Opportunities
The United States : Largest Market for Pediatric Drugs and Vaccines
Developing Markets to Witness Faster Growth
Table 5: Healthcare Spending as a Percentage of GDP by Region (2016E) (includes corresponding Graph/Chart)
Table 6: Per-Capita Healthcare Expenditure in US$ for Select Countries/Regions (2014) (includes corresponding Graph/Chart)
Table 7: Developing Regions Lead Children Population Globally (includes corresponding Graph/Chart)
Table 8: Global Under 15 Years Population (2016): Percentage Breakdown by Gender (includes corresponding Graph/Chart)
Table 9: Population of Children in the Age Group of 0-15 Years as a Percentage of Total Population by Region/Country (2016) (includes corresponding Graph/Chart)
Table 10: Proportion of Children in the 0-15 Years Age Group by Country in Europe (2016) (includes corresponding Graph/Chart)
Table 11: Proportion of Children in the 0-15 Years Age Group by Country in Asia-Pacific (2016) (includes corresponding Graph/Chart)
Table 12: Proportion of Children in the 0-15 Years Age Group by Country in Latin America (2016) (includes corresponding Graph/Chart)
Table 13: Proportion of Children in the 0-15 Years Age Group by Country in the Middle East (2016) (includes corresponding Graph/Chart)
Antibiotics: Largest Selling Drug Classes
Table 14: Global Pediatric Drugs Market by Therapeutic Class: Segments Ranked by Growth (includes corresponding Graph/Chart)
Pediatric Vaccines Market - On High Growth Trajectory
Supply and Demand Dynamics of the Global Vaccine Market
Table 15: Global Vaccine Market by Countries' Economic Status (2016): Percentage Share Breakdown for High-income, Middle-Income (Upper & Lower), and Low-income Nations (includes corresponding Graph/Chart)
UNICEF Addresses BCG Vaccine Supply Shortage
Access to Vaccines Index: Aiding Increased Access to Vaccines
Recent Advancements/Achievements in the Pediatric Vaccines Space

2. GROWTH DRIVERS AND MARKET TRENDS
Pediatric Exclusivity Drives Manufacturers' Interest
Pediatric Exclusitivity Granted to Branded Drugs
New Product Approvals and Pipeline - A Key Growth Propeller
Recent Pediatric Drug Approvals: 2015-2017
Pediatric Drug Approvals: 2011-2014
Phase III Completed Pediatric Drugs: 2015-2017 (As of July 2017 )
Ongoing Phase III Pediatric Drugs Clinical Trials: 2015-2017 (As of July 2017 )
Potential for Pediatric Drugs Against Obesity-related Conditions
Table 16: Top 10 Countries with the Highest Proportion of Overweight Children (includes corresponding Graph/Chart)
List of Pediatric Drugs for Congestive Heart Failure Treatment
Recent Findings to Help Save Children's Lives
Challenges of Pediatric Drug Development: Formulation Problems and Ethical Constraints of Clinical Trials
Financial Enticement for Drug Makers to Conduct Dedicated Pediatric Trials
Modeling & Simulation - A Powerful Tool for Pediatric Clinical Study Sponsors
Pharmacometrics Approaches Gain Traction Among US and EU Researchers
Challenges Associated with Adoption of Pharmacometric Approach
Guidelines for Conducting Ethically Correct Clinical Trials
Pediatric Drug Market - Is Off-label Prescription Justified?
Indian Drug Manufacturers Develop Pneumococcal Conjugate Vaccine
High Vaccination Costs: A Major Hindrance for Pneumonia Vaccination
Vaccine Refusal by Parents - A Growing Trend in the US Market
Orphan Drugs for Pediatric Use Gain Popularity
List of FDA Approved Orphan Drugs: 2015-2016
List of FDA Designated Orphan Drugs: 2015-2017
Pediatric Review Vouchers Foster Innovation in Rare Pediatric Drugs
Need for Higher Focus on Fixed-Dose Combination for Pediatric HIV Infections
Approved Pediatric Antiretroviral Drugs for HIV Treatment
Highly Fragmented Growth Hormone Market

3. PEDIATRIC VACCINES MARKET
Table 17: Number of Reported Cases for Vaccine-Preventable Diseases Globally: 2013-2016
Table 18: Percentage of Target Population Vaccinated, by Antigen: 2013-2015 (includes corresponding Graph/Chart)
Immunization Coverage
Table 19: Routine Immunization Coverage (2015): Percentage of Live Births/New Borns/Infants/ Children Vaccinated by Select Region
Market Share of Leading Pediatric Vaccine Manufacturers
Table 20: Global Pediatric Vaccines Market by Leading Players (2016E): Percentage Market Share Breakdown of Dollar Sales for GlaxoSmithKline, Sanofi-Pasteur, Merck, Pfizer, and Others (includes corresponding Graph/Chart)
Phase III Completed Pediatric Vaccines: 2015-2017 (As of July 2017 )
Ongoing Phase III Pediatric Vaccines Clinical Trials: 2015- 2017 (As of July 2017 )
Pediatric Vaccine Types
Hemophilus Influenza Type B Vaccine
Available Hib and Combination Vaccines
Diphtheria/Tetanus/Pertussis Vaccines (DTaP Vaccines)
Available DTaP and Combination Vaccines
Table 21: Global DTP3 Immunization Coverage: 2005-2015 (includes corresponding Graph/Chart)
Table 22: DTP3 Immunization Coverage, 2015 (includes corresponding Graph/Chart)
Hepatitis A Vaccine
Hepatitis B Vaccine
Hepatitis B Epidemiology
Available Hepatitis A and B & Combination Vaccines
Measles/Mumps/Rubella (MMR) Vaccines
Available MMR and Combination Vaccines
Rotavirus Vaccines
Available Rotavirus Vaccine
Polio Vaccines
Available Polio and Combination Vaccines
Varicella Virus Vaccine (VAR)
Available Varicella Vaccines
Pneumococcal Disease Vaccines
PCV 13 Replaces PCV 7
Available Pneumococcal Conjugate Vaccine
Meningococcal Vaccines
Available Meningococcal Polysaccharide and Combination vaccine
Combination Vaccines
Hepatitis B Combination Vaccines to Propel Market Growth
Table 23: Number of Countries Having Introduced HepB Vaccine: 2005-2015 (includes corresponding Graph/Chart)
Table 24: Global Infant HepB3 Coverage: 2005-2015 (includes corresponding Graph/Chart)
Rising Women Workforce Propels Pediatric Vaccines Growth
Table 25: Female Employment-to-Population Ratio (%): 2002, 2007, 2012, & 2016 (includes corresponding Graph/Chart)

4. PEDIATRIC DISEASES - OVERVIEW, STATISTICS & TREATMENT
Influenza
Treatment
Urinary Tract Infection (UTI)
Prevalence
Treatment
Mumps
Complications Related to Mumps
Prevention of Mumps in children
Incidence
Candidiasis
Fifth Disease
Molluscum Contagiosum
Roseola
Tetanus
Whooping Cough
Allergy and Respiratory Diseases
Prevalence Statistics
The US
Other Countries
Diphtheria
Incidence and Mortality Statistics
Upper Respiratory Infection (Common Cold)
Diagnosis & Treatment
Measles
Statistics
Asthma
Prevalence
Central Nervous System Disorders
Mental Disorders
Prevalence
Attention Deficit Hyperactivity Disorder
Prevalence
Depression
Prevalence
Epilepsy
Epilepsy Treatment
Incidence and Prevalence of Epilepsy in the US
Hormonal Disorders
Diabetes Mellitus
Hypothyroidism
Hypothyroidism in Infants and Children
Symptoms and Diagnosis
Treatment of Hypothyroidism in Children
Precocious Puberty
Symptoms and Signs
Signs of Early Puberty in Girls and Boys
Treatment
Hypopituitarism
Treatment
Lymphocytic Thyroiditis
Symptoms
Treatment
Other Diseases
Cardiovascular Diseases
Hypertension
Causes of Hypertension in Children
Symptoms of High Blood Pressure
Treatment
Cancers
Brain Tumors
Prevalence
Leukemia
Prevalence
Lymphomas
Prevalence
Retinoblastoma
Prevalence
Ewing's Sarcoma
Symptoms and Treatment
Prevalence
Wilms' Tumor
Stages and Treatment
Prevalence & Incidence
Children's Rhabdomyosarcoma
Symptoms and Signs
Treatment
Statistics
Neuroblastoma
Symptoms
Treatment
Osteogenic Sarcoma
Prevalence
Symptoms and Treatment
Diarrhea
Inflammatory Bowel Disease (IBD)
Symptoms
Treatment
Irritable Bowel Syndrome (IBS)
Causes & Symptoms
Treatment
Pain
Pain Control Medicines for Children
Statistics
Pain Statistics Among the American Children, General Population, and Other Adults
Malaria
Anemia
Treatment for Anemia in Children

5. LIST OF SELECT FDA APPROVED PEDIATRIC DRUGS

6. PRODUCT INTRODUCTIONS/APPROVALS
Actelion Obtains "Epoprostenol Act" Label Extension for Pediatric PAH Patients in Japan
FDA Approves Merck's KEYTRUDA® (pembrolizumab)
Novartis Announces FDAs Acceptance of Company's CAR-T Cell Therapy BLA for Pediatric and Young Adult Patients with r/r B-cell ALL
Boehringer Ingelheim's Tiotropium Respimat® Receives FDA Approval Expansion for Maintenance Treatment of Asthma in Children
Sanofi Pasteur terminates a Vaccine Joint-venture with MSD
ViiV Healthcare Announces the Changed Opinion of CHMP to Lower the Age and Weight Limit for Tivicay® (dolutegravir) in Children and Adolescents Living with HIV in Europe
Shire Announces FDA Approval of ADYNOVATE® [Antihemophilic Factor (Recombinant), PEGylated] for Use in Children and Surgical settings
Pfizer Inc. Announces PHASE 3 TRIALs Positive Results of LYRICA® (PREGABALIN) Capsules CV and Oral Solution CV for Treating Pediatric Epilepsy Patients
Pfizer's Prevenar 13® Receives Approval for Use in Infants and Children in China
Simponi® Receives European Commission Approval for Treatment of Polyarticular Juvenile Idiopathic Arthritis
Sanofi Pasteur Launches India's first innovative 6-in-1 vaccine
Shire launches pediatric indication for immunodeficiency treatment HyQvia in Europe
Novo Nordisk's NovoRapid® receives positive opinion from CHMP for extended use in European Union for children as young as one year old
Boehringer Ingelheim Announces the Ability of Tiotropium Respimat® for improving lung function in children aged 6-11
FDA Approves BLINCYTO® (blinatumomab) for Use in Pediatric Patients with Philadelphia Chromosome-Negative Relapsed or Refractory B-cell Precursor Acute Lymphoblastic Leukemia
FDA Approves Genentech's Xolair® (omalizumab) for Allergic Asthma in Children
Novartis Receives EU Approval for Revolade® as First-in-class Therapy for Children Aged 1 year and above with Chronic ITP
Pandemic Influenza Vaccine Receives Positive Opinion from CHMP
GSK's Advair® Diskus® Exhibits Primary Endpoint in paediatric 'LABA' Safety Study
FDA Accepts Amgen's Supplemental Biologics License Application (sBLA) for The Expanded Use Of Enbrel® (Etanercept) To Treat Pediatric Patients with Chronic Severe Plaque Psoriasis
Genentech's supplemental Biologics License Application (sBLA) Receives Acceptance from FDA for reviewing Xolair® ( omalizumab)
Shire Partner, Shionogi, Submits New Drug Application in Japan for ADHD treatment for children
Shire Reports Topline Results from Phase 2 Studies in Children with Alagille Syndrome
FDA approves first drug to treat a rare enzyme disorder in pediatric and adult patients for Immediate Release
Sanofi K.K. and Aptalis Pharmaceutical Technologies Launches Allegra Dry Syrup 5% in Japan
Sanofi Pasteur Announces Availability of First Doses of Injectable Polio Vaccine ShanIPV(TM) in Near Future for Indian Infants
Shire receives CHMP's Positive Opinion in Europe for INTUNIV®
Novo Nordisk's Levemir® Receives Positive Opinion from CHMP for Extended use in Children as Young as one Year Old

7. RECENT INDUSTRY ACTIVITY
Johnson & Johnson Acquires Actelion
Sanofi Collaborates with MedImmune for development and Commercialization of Monoclonal Antibody for Preventing RSV
GSK Intends to Opens a New Global Vaccines R&D Center in Rockville, MD , USA
Lupin and Monosol Rx Enters into Licensing Agreement for Developing Multiple Pediatric-Focused Products
ICGEB & Sun Pharma Enters into New Exclusive Collaboration to Develop Novel Dengue Vaccine for India & Global Markets
Actelion Initiates Phase III Study of Macitentan (Opsumit) for treating Children with PAH
Shire and Cincinnati Children's Establishes Rare Disease Research Collaboration

8. FOCUS ON SELECT GLOBAL PLAYERS
Abbott Laboratories ( USA )
Allergan, Inc. ( USA )
Amgen, Inc. ( USA )
AstraZeneca Plc. (UK)
Boehringer Ingelheim GmbH ( Germany )
Bristol-Myers Squibb Company ( USA )
Eli Lilly and Company ( USA )
F. Hoffmann-La Roche Ltd ( Switzerland )
Genentech, Inc. ( USA )
GlaxoSmithKline plc. (UK)
Janssen Biologics B.V. ( USA )
Actelion Pharmaceuticals Ltd ( Switzerland ) (A Janssen Pharmaceutical Company)
Merck & Co., Inc. ( USA )
Novartis AG ( Switzerland )
Novo Nordisk A/S ( Denmark )
Pfizer, Inc. ( USA )
Sanofi S.A ( France )
Shionogi Inc. ( USA )
Shire Pharmaceuticals Group Plc. (UK)

9. GLOBAL MARKET PERSPECTIVE
Table 26: World Recent Past, Current & Future Analysis for Pediatric Drugs and Vaccines by Geographic Region - US, Canada , Japan , Europe , Asia-Pacific , Latin America , and Rest of World Markets Independently Analyzed with Annual Sales Figures in US$ Million for Years 2016 through 2024 (includes corresponding Graph/Chart)
Table 27: World Historic Review for Pediatric Drugs and Vaccines by Geographic Region - US, Canada , Japan , Europe , Asia-Pacific , Latin America , and Rest of World Markets Independently Analyzed with Annual Sales in US$ Million for Years 2011 through 2015 (includes corresponding Graph/Chart)
Table 28: World 14-Year Perspective for Pediatric Drugs and Vaccines by Geographic Region - Percentage Share Breakdown of Dollar Sales for US, Canada , Japan , Europe , Asia-Pacific , Latin America , and Rest of World Markets for Years 2011, 2017& 2024 (includes corresponding Graph/Chart)
Pediatric Vaccines Market by Therapeutic Segment
Table 29: World Recent Past, Current & Future Analysis for Pediatric Vaccines by Geographic Region - US, Canada , Japan , Europe , Asia-Pacific , Latin America , and Rest of World Markets Independently Analyzed with Annual Sales in US$ Million for Years 2016 through 2024 (includes corresponding Graph/Chart)
Table 30: World Historic Review for Pediatric Vaccines by Geographic Region - US, Canada , Japan , Europe , Asia-Pacific , Latin America , and Rest of World Markets Independently Analyzed with Annual Sales in US$ Million for Years 2011 through 2015 (includes corresponding Graph/Chart)
Table 31: World 14-Year Perspective for Pediatric Vaccines by Geographic Region - Percentage Share Breakdown of Dollar Sales for US, Canada , Japan , Europe , Asia-Pacific , Latin America , and Rest of World Markets for Years 2011, 2017 & 2024 (includes corresponding Graph/Chart)
Table 32: World Recent Past, Current & Future Analysis for Pediatric Hormones by Geographic Region - US, Canada , Japan , Europe , Asia-Pacific , Latin America , and Rest of World Markets Independently Analyzed with Annual Sales in US$ Million for Years 2016 through 2024 (includes corresponding Graph/Chart)
Table 33: World Historic Review for Pediatric Hormones by Geographic Region - US, Canada , Japan , Europe , Asia-Pacific , Latin America , and Rest of World Markets Independently Analyzed with Annual Sales in US$ Million for Years 2011 through 2015 (includes corresponding Graph/Chart)
Table 34: World 14-Year Perspective for Pediatric Hormones by Geographic Region - Percentage Share Breakdown of Dollar Sales for US, Canada , Japan , Europe , Asia-Pacific , Latin America , and Rest of World Markets for Years 2011, 2017 & 2024 (includes corresponding Graph/Chart)
Table 35: World Recent Past, Current & Future Analysis for Pediatric Allergy & Respiratory Drugs by Geographic Region - US, Canada , Japan , Europe , Asia-Pacific , Latin America , and Rest of World Markets Independently Analyzed with Annual Sales in US$ Million for Years 2016 through 2024 (includes corresponding Graph/Chart)
Table 36: World Historic Review for Pediatric Allergy & Respiratory Drugs by Geographic Region - US, Canada , Japan , Europe , Asia-Pacific , Latin America , and Rest of World Markets Independently Analyzed with Annual Sales in US$ Million for Years 2011 through 2015 (includes corresponding Graph/Chart)
Table 37: World 14-Year Perspective for Pediatric Allergy & Respiratory Drugs by Geographic Region - Percentage Share Breakdown of Dollar Sales for US, Canada , Japan , Europe , Asia-Pacific , Latin America , and Rest of World Markets for Years 2011, 2017 & 2024 (includes corresponding Graph/Chart)
Table 38: World Recent Past, Current & Future Analysis for Pediatric Antibiotics by Geographic Region - US, Canada , Japan , Europe , Asia-Pacific , Latin America , and Rest of World Markets Independently Analyzed with Annual Sales Figures in US$ Million for Years 2016 through 2024 (includes corresponding Graph/Chart)
Table 39: World Historic Review for Pediatric Antibiotics by Geographic Region - US, Canada , Japan , Europe , Asia-Pacific , Latin America , and Rest of World Markets Independently Analyzed with Annual Sales in US$ Million for Years 2011 through 2015 (includes corresponding Graph/Chart)
Table 40: World 14-Year Perspective for Pediatric Antibiotics by Geographic Region - Percentage Share Breakdown of Dollar Sales for US, Canada , Japan , Europe , Asia-Pacific , Latin America , and Rest of World Markets for Years 2011, 2017 & 2024 (includes corresponding Graph/Chart)
Table 41: World Recent Past, Current & Future Analysis for Pediatric CNS Drugs by Geographic Region - US, Canada , Japan , Europe , Asia-Pacific , Latin America , and Rest of World Markets Independently Analyzed with Annual Sales in US$ Million for Years 2016 through 2024 (includes corresponding Graph/Chart)
Table 42: World Historic Review for Pediatric CNS Drugs by Geographic Region - US, Canada , Japan , Europe , Asia-Pacific , Latin America , and Rest of World Markets Independently Analyzed with Annual Sales in US$ Million for Years 2011 through 2015 (includes corresponding Graph/Chart)
Table 43: World 14-Year Perspective for Pediatric CNS Drugs by Geographic Region - Percentage Share Breakdown of Dollar Sales for US, Canada , Japan , Europe , Asia-Pacific , Latin America , and Rest of World Markets for Years 2011, 2017 & 2024 (includes corresponding Graph/Chart)
Table 44: World Recent Past, Current & Future Analysis for Other Pediatric Drugs by Geographic Region - US, Canada , Japan , Europe , Asia-Pacific , Latin America , and Rest of World Markets Independently Analyzed with Annual Sales in US$ Million for Years 2016 through 2024 (includes corresponding Graph/Chart)
Table 45: World Historic Review for Other Pediatric Drugs by Geographic Region - US, Canada , Japan , Europe , Asia-Pacific , Latin America , and Rest of World Markets Independently Analyzed with Annual Sales in US$ Million for Years 2011 through 2015 (includes corresponding Graph/Chart)
Table 46: World 14-Year Perspective for Other Pediatric Drugs by Geographic Region - Percentage Share Breakdown of Dollar Sales for US, Canada , Japan , Europe , Asia-Pacific , Latin America , and Rest of World Markets for Years 2011, 2017 & 2024 (includes corresponding Graph/Chart)
Table 47: World Recent Past, Current & Future Analysis for Pediatric Vaccines by Type - Combinations, Hepatitis, MMR, Varicella, Poliovirus, Pneumococcal, and Other Markets Independently Analyzed with Annual Sales in US$ Million for Years 2016 through 2024 (includes corresponding Graph/Chart)
Table 48: World 9-Year Perspective for Pediatric Vaccines by Type - Percentage Share Breakdown of Dollar Sales for Combinations, Hepatitis, MMR, Varicella, Poliovirus, Pneumococcal, and Other Markets for Years 2017 & 2024 (includes corresponding Graph/Chart)


The prime-boost approach

Current vaccination traditionally known to be effective requires immunization of an individual with two or more doses and this consists of a “prime-boost regime”. As the vaccines used in the prime and boost consist of the same formulation, such regime is called homologous prime-boost. On the other hand, an immunization regime involving different formulations used sequentially in more than one administration will be called heterologous prime-boost. Research results accumulated over the past decade have shown that heterologous immunization can be more effective than homologous immunization, especially against intracellular pathogens, the infectious agents of higher complexity that are currently considered to be more challenging for vaccine development (59).

The heterologous prime-boost or simply “prime-boost” immunization, as it is commonly called, is a strategy, which involves the administration of the same antigens but formulated in different ways, either as purified antigens or recombinant protein in the presence of appropriate adjuvants, as live recombinant viral or bacterial vectors or DNA vaccines. This approach has opened new venues for vaccine development, and appears to be able to induce a more adequate and efficient immune response against intracellular pathogens. The idea behind the heterologous prime-boost immunization is to combine both humoral and cellular immunity, potentially elicited by each delivery system individually, in an attempt to enhance and modify the immune response induced against a specific antigen. For example, subunit vaccines will usually induce a predominant humoral immune response, while recombinant live vector vaccines and DNA vaccines are effective delivery systems for eliciting cell-mediated immunity (CMI) (59).

The great potential of this strategy has been well demonstrated in the context of HIV vaccine development. Monkeys (Macaca fascicularis) primed with the recombinant vaccinia virus expressing SIVmne gp160 antigen and boosted with the recombinant gp160 protein were protected against an intravenous challenge with SIVmne virus. These results were considered among the most promising obtained in the early effort of HIV vaccine development (60). On the other hand, the combination of DNA vaccines with other immunization approaches has also proven to induce greatly increased immunogenicity. Mice primed with a DNA vaccine encoding the hemagglutinin gene of influenza and boosted two weeks later with a recombinant viral vector Fowl poxvirus (FPV) expressing the same antigen were able to produce high levels of anti-hemagglutinin serum antibodies, predominantly of the IgG2a isotype, unlike animals immunized with each vector alone (61).

Since these seminal investigations, several groups have obtained good results using either similar combinations or alternative protocols (62). Many different combinations of heterologous prime-boost will be possible: DNA vaccine-recombinant protein live recombinant bacteria/virus-recombinant protein live recombinant bacterial/virus-DNA vaccine (and vice versa). However, in spite of some positive results, in general prime-boost immunization protocols initiating with recombinant vectors followed by recombinant protein have produced disappointing results (63). Interestingly, the order of the prime and boost has been shown to alter the immune response obtained. In a prime-boost strategy of immunization against malaria, mice immunized with consecutive DNA and MVA vectors encoding antigens from Plasmodium berghei have been shown to be protected against challenge with P. berghei sporozoites, and such protection was associated with high levels of peptide-specific IFN-γ-secreting CD8 + T cells. However, reversal of the order of the immunization or substitution of the viral vector resulted in failure of protection (64). This result showed the importance of using DNA as a priming vehicle and attenuated virus as a booster.

Prime-boost strategies have been applied for the development of vaccines against important infectious diseases such as HIV, TB, and malaria, demonstrating promising results even in clinical trials. In the last HIV clinical trial using a combination of two earlier vaccines that had previously failed, researchers found that the prime-boost combo reduced by 31% the risk of contracting HIV (65). Unfortunately, they have also shown that the observed protection was limited to 1 year. In spite of this short-lived protection, the authors believe this result is encouraging and that a new and safer HIV vaccine will soon be available. Presently, clinical trials are ongoing to further assess this line of research (66).

The exact mechanism underlying the efficacy of the heterologous prime-boost vaccination is still poorly understood, being likely that several distinct mechanisms participate in the success of this approach. One mechanism proposed suggests that the different characteristics of the vectors are important. A second advantage of a heterologous prime-boost is the fact that the use of different immunization strategies results in reduced induction of anti-vector immunity. A third, and possibly the most relevant mechanism, is due to immunodominance. During priming immunization, T cells will be induced against the most immunodominant epitopes of the antigen. Upon heterologous boosting, which shares only the relevant antigen with the prime immunization, the immune response will focus preferentially on the expansion of immunodominant T cells induced by priming (67,68) live recombinant vectors, such as MVA and adenovirus, seem to be especially efficient in boosting pre-existing memory immune responses, especially primed T-cell responses (65,66,69).

A number of studies have shown that at least one plasmid vector (consisting of DNA vaccine) or a recombinant viral vector should be included as a component of the prime-boost vaccination in order to elicit a potent cell-mediated immunity (59,64,70). Although DNA vaccines so far have shown low immunogenicity when used alone, they have also proven to act as strong priming vehicles, while viral vectors seem to be much more effective when used as boosters. As a consequence, DNA prime-viral vector boost regimes have become the main scheme of choice to induce T cell-mediated immune responses (59,64,70).

One possible mechanism to explain the success of these prime-boost regimes relies on the induction of high-avidity T cells. Mice immunized with DNA prime/live vector boost protocols expressed high frequencies of high-avidity T cells and were capable of eliminating target cells expressing 10- to 100-fold less immunogenic peptide than mice vaccinated with either vector alone (70). Other features characteristic of the vaccine vectors used in prime-boost immunization may as well be essential for their ability to induce increased CMI ( Table 2 ). The presence of cytosine-phosphodiester bond-guanine (CpG) motifs in the plasmid of the DNA vector has also been shown to strongly stimulate the production of IL-12, the main inducer cytokine of Th1 cells. The use of non-replicating DNA vaccines followed by live vectors may result in an immune response focused almost exclusively on the encoded antigen. The efficient presentation of the encoded antigen by MHC class I and class II molecules will result in efficient induction of CD4 + T and CD8 + T cells (70). The types of antigens and the types of vectors used, the order of vector administration, the routes and interval between priming and boosting vaccinations, among other factors, should be taken into account to determine the effectiveness of the prime-boost strategies ( Table 1 ). Further investigation of the mechanism of action of this promising strategy will allow its optimization, and eventually lead to improved vaccines.

Table 2.

VectorPropertiesImmune consequenceMost used vaccinationReferences
PrimeBoost
DNA vaccineEncoded antigens delivered to MHC class I and class II processing pathwaysCD4 + Th1 and CD8 + T cellsDNAViral59,61,63,64,70
Low level and constant expression of proteinProlonged immune stimulation and induction of high-affinity T cells BCG59,63,64
Presence of CpG motifsAdjuvant for CMI RP/Adj59,63,64
Expresses only vaccine antigenFocused response on antigen
ViralEfficient delivery to MHC class I and class II process pathwaysExpansion of T-cell responses induced by DNA vaccinationViralRP/Adj59,60,63,64
Higher levels of encoded antigenExpansion of high-affinity T cells primed by DNA vaccine
Presence of CpG motifs and other TLR agonistsAdjuvant for CMI and strong production of pro-inflammatory cytokines
Non-productive replication in mammalian cellsImmune response largely focused on encoded antigen and safe for human use
Bacterial (BCG)Encoded antigens delivered to MHC class II processing pathwaysInduction of CD4 + Th1/Th2 cellsBacterialViral59,63,64,70
Recombinant proteinRequires adjuvant and multiple immunizationsCD4 T cell and humoral responsesRP/AdjRP/Adj59,63,64
Requires strong adjuvantPoor induction of cellular responses, particularly of CD8 + T cells

Keep Doing It

As I mentioned above, most people with any health ailments are perfectly capable of restoring their health to a much better place through diet alone. This includes vaccine damage. If you’ve had a vaccine, you have been damaged by the vaccine. The question is to what degree and whether the body already compensated or healed from it.

The benefit of concentrated herbal and supplemental therapy is their ability to speed up the healing and detoxification process. But most of these protocols do very little for most people when their diet is not right. The worse the diet is, the more supplements are going to be needed to compensate, up to the point at which the diet is so bad that supplements, at best, are merely slowing the decay of the body.

For those who are very sick and cannot function well enough to eat a well-balanced diet, a supplement protocol may be the difference between life and death, or at least, a miserable life and getting well.

These processes must not be hindered by medication aimed at suppressing the symptoms. While it may not be wise to stop taking medications under certain circumstances, the best one can hope for with even the most radical detox and nutrition overhaul program (such as this) is a body that works better. But to actually be healthy, one cannot continue consuming high levels of toxins such as pharmaceuticals.

Some of the above therapies will not apply, and many together may be overkill for the average person just looking to detox on a budget. But take your pick and pull what works for you. Or if you’re particularly ill, do your best to understand the whole process, and incorporate as much as you can that works for your budget and your health. Regardless of the ailment, this protocol can heal almost everyone if practiced long enough. Vaccines damage us from many different angles, and a holistic approach to healing is critical to reverse the damage.

Multiple injuries from vaccinations require each injury or disease to take its own time to heal and be cleared from the system. As the immune system becomes more in balance, it will be able to clear toxicity. Allergic symptoms will diminish and cognitive function will increase as the vaccine ingredients that the body is reacting too are expelled. Be sure to see the further reading below for more information.

Don’t let the supplement list below scare you. Most people can fully detoxify and recover from vaccines with the right diet and very little if any extra nutritional support if given enough time. This is especially true from people who were healthy, to begin with. If you need to detox from vaccines on a tight budget, check this nutrition formula recipe and see these recipes here as well. Take SF722 and Abzorb. If you’re overwhelmed or want to pick a few more of the best supplements for your issues, talk to Green Lifestyle Market about your budget and concerns. Eating right is paramount, and when it comes to healing, supplements are not very effective for very long without a proper diet. If you suffer from any autoimmune health issues, vaccine-related or not, be sure to check out Best Supplements To Kill Candida and Everything Else You Ever Wanted To Know About Fungal Infections. Anyone who suffers from chronic illness is dealing with an abundance of Candida, and the body will not get well until the gut is balanced.

Diet is critical – even more important than the supplements. See the diet articles below. Eat a diverse large salad every day. Recipes are included below.


Protein and Vaccine Production

Protein and vaccine production is commonly used by the pharmaceutical industry to generate bio-therapeutic products.

Protein Therapeutics

Therapeutic proteins are commonly engineered in pharmaceutical laboratories to generate human protein therapeutics. The first protein therapeutic was insulin derived from recombinant DNA in 1982. Bacteria expression systems and mammalian cell lines such as Chinese Hamster Ovarian (CHO) are used to produce therapeutic proteins, antibodies, enzymes or hormones that can be injected into humans or animals to treat diseases.

Vaccine Therapeutics

Virus production to produce vaccine particles to stimulating the immune system is a classic approach. When using vaccines for gene therapy the utilization of the virus is slightly different, it will act as a gene delivery vector, the three most common viruses vectors are:

  • Retroviruses (for insertion of DNA ex-vivo or in-vivo)
  • Adenoviruses (for transient expression)
  • Lentiviruses (for ex-vivo transient and stable gene expression)

Pharmaceutical companies use one or more bio-therapeutic methods to treat or potentially cure a disease.

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What is protein production?

Protein production systems, also referred to as an expression system, are commonly utilized by the pharmaceutical industry to produce novel medicines. Protein production is the biotechnological process of generating a specific protein. It is achieved by the manipulation of gene expression in an organism such that it expresses large amounts of a recombinant gene. This expression process includes the transcription of the recombinant DNA to messenger RNA (mRNA). When the mRNA is translated into polypeptide chains, the chain folds into functional proteins and can then be targeted to specific subcellular or extracellular locations.

Protein production, to produce a protein or antibody of interest, is a multi-step process.

Steps to take before starting protein production

Steps required before starting protein production

Target identification

Target validation

Hit identification and lead generation (H2L)

Lead optimization

Preclinical testing

Clinical phase

  • Phase I &ndash first human studies &ndash mainly safety testing on healthy persons
  • Phase II &ndash testing different doses on patients
  • Phase II &ndash expand test panel, efficacy, and meet primary and secondary endpoints
  • Phase IV &ndash post marketing safety study, tackle safety concerns, different populations, and sometimes-rare side effects

Market ready

Which expression system to choose for protein production

Many organisms can produce proteins. See the table below for major organisms and important cellular characteristics.

Microorganisms, like Escherichia coli (E. coli) are easy to grow and express high levels of protein. So why is E.coli not always the ideal choice when producing recombinant proteins? The limitation lies within the protein folding process and the ability to produce complex proteins such as glycosylated proteins. Therefore, mammalian cell platforms are often utilized for complex protein production (posttranslational modifications &ndash PTM). Although these mammalian cells may not proliferate as rapidly and may not yield as much protein as E.coli, these platforms are often selected for complex protein production to deliver protein therapeutics (i.e. biologics) in the biotech sector.

Transient or Stable transfection for protein production

  • Transient transfection is ideal for the rapid production for small scale antibody (Ab) production. Transient gene expression results are often realized in 6-10 days from the initiation of DNA transfection.
  • Stable transfection often begins transiently but through a process of careful selection and amplification, stable clones are generated. Within stable transfected cells, the foreign gene becomes part of the host genome and is therefore replicated. Descendants of these transfected cells express the foreign gene and become a stable cell line. Because this transfection process is complex and time consuming, it is more often used for large scale Ab production.

Products produced using protein production

There are a variety of products that can be produced via protein production:

  • Modified human proteins (protein-protein fusion products, drug-toxin conjugates, PEGylated protein drugs)
  • Monoclonal antibodies (humanized or chimeric monoclonal antibodies, monoclonal antibody fragments, single chain antibodies, bispecific antibodies, antibodies to conjgate to a toxic payload (ADCs).
  • Growth factors and cytokines (colony stimulating factors, interferons, interleukins)
  • Hormones (insulin, erythropoietin, growth hormones)
  • Blood products (blood clotting factors, thrombolytics, fibrinolytics, albumin)

Protein production methods

A protein can be produced in different ways:

Batch protein production

This is a large-scale closed culture system where cells are expanded in a fixed volume of medium with no additional additives. Since fresh media is not added during the incubation period, the concentration of nutrition decrease throughout expansion and various toxic metabolites accumulate. A batch culture will follow the characteristics growth curve with lag phase, log phase, stationary phase and decline phase.

*These processes are only appropriate for proteins that are excreted into the media, ie this method is not applied to intracellular expression proteins.

Fed-batch protein production

A semi closed system for protein production where one or more nutrients (feeds) are added in intervals into a bioreactor. The product(s) remain in the bioreactor throughout the production process.

Perfusion protein production

Perfusion carried out by continuously feeding fresh medium into the bioreactor and simultaneously removing the cell-free spent medium as the cells expand in the bioreactor. The cell density remains constant by maintaining a constant dilution and flow rate.

A vaccine is a biological preparation that is made up of very small amount of weak or dead germs that can cause diseases. (1) It prepares your body to fight the disease faster and more effectively so you won&rsquot get sick (1). This biological preparation made from vaccine manufacturing, stimulates the body's immune system to recognize the agent as a threat, destroy it, and to further recognize and destroy any of the microorganisms associated with that agent that it may encounter in the future (2). Viral particles, a key component for many vaccine classes, can be employed for either prophylactic or therapeutic applications. While viral particle manufacturing has classically focused on producing vaccines that are used to stimulate the immune system, an increasing interest in viral particle manufacturing for use as gene delivery vectors for cell and gene therapy has been driving growth and acceleration in this field.