Vaccines

Benefits of Vaccine Adjuvants

- Adding an adjuvant reduces the amount of the active component required in a vaccine. a) Reducing the cost per vaccine b) Making more doses available for public use - A person may need fewer doses of a vaccine containing an adjuvant -> the immune response is stronger and lasts longer - People with compromised immune systems, such as the elderly or the very young, benefit from vaccines with adjuvants --> their immune systems require an extra boost to provide protection - Adjuvants are especially effective in boosting the immune-stimulating effects of newer vaccines, such as those made with purified antigens.

Adjuvants

- An adjuvant is a substance that, when added to a vaccine, greatly enhances its protection against infection a) "adjuvant" comes from the latin word adjuvare, meaning "to help" - Alum, a mixture of aluminum salts, was the first vaccine adjuvant to be widely used in the United States a) It was the only vaccine adjuvant in use until 2009 b) The FDA approved Cervarix (2009), a human papillomavirus vaccine that contains an adjuvant called AS04. --> AS04 is a mixture of alum and bacterial lipid molecule that has been modified so that it does not cause disease.

Advantages of Live Attenuated Viral Vaccines

- Better immunity b/c vaccine actually produces a limited infection - Can spread the attenuated virus to contacts - "herd immunity": the phenomenon whereby those people who have no immunity against a particular pathogen are largely protected because the majority of the population is immune.

Polio Eradication and Endgame Strategic Plan 2013-2018

- By the end of 2015, introduce at least 1 dose of IPV into all routine immunization systems, at least 6 months before the switch from trivalent oral polio vaccine (tOPV) to bivalent oral polio vaccine (bOPV, containing types 1 and 3 poliovirus) - During 2016, switch from tOPV to bOPV, which does not contain type 2 virus, in routine immunization and polio campaigns. Type 2 virus has not been identified in any WPV cases and has been officially eradicated since 1999 - Plan for the eventual withdrawal of all OPV. (target 2018-2019)

Vaccinia vs. Smallpox

- Cowpox and smallpox viruses share some surface antigens - Immunization with cowpox induces antibodies against cowpox surface antigens. - Cowpox antibodies bind to and neutralize the smallpox virus.

RTS S/AS01 Phase 3 Trial

- Enrolled 15,460 infants and young children in seven sub-Saharan African countries (Burkina Faso, Gabon, Ghana, Kenya, Malawi, Mozambique, and the United Republic of Tanzania) - These countries represent a range of different malaria transmission settings in order to be able to determine the vaccine's usefulness in these different settings

American Academy of Pediatrics: Updated Guidelines 2012

- Girls aged 11 to 12 years should be routinely immunized using 3 doses of the HPV4 or HPV2 vaccine, administered intramuscularly at 0, 1 to 2, and 6 months. - Girls and women aged from 13 to 26 years who have not been previously immunized or who have not completed their vaccinations should finish the series. - Boys aged 11 to 12 years should be routinely immunized with HPV4, using the same schedule as for girls. - Boys and men aged from 13 to 21 years who have not already been immunized or who have not completed their vaccines should finish the series. - Men aged from 22 to 26 years who have not already been immunized or who have not finished the full series may be administered the recommended vaccine. (The AAP guidelines note that "cost-efficacy models do not justify a stronger recommendation in this age group.") -Special efforts should be made to target use of the vaccine in gay or bisexual men up to 26 years of age who have not previously received the vaccine. - People infected with HIV should be vaccinated or complete their series of vaccinations. - The vaccine is not recommended during pregnancy, nor should it be administered to individuals with a known immediate hypersensitivity to yeast. However, it may be administered during lactation, as well as to those who are immunocompromised from either illness or medication

Polio Eradication

- Last case in US in 1979 - Western Hemisphere certified polio free in 1994 - Last isolate of type 2 poliovirus in India, 1999 - Global eradication goal by 2005 - "In the last 15 years, the number of cases of polio worldwide has dropped spectacularly, going from 350,000 cases in 1988 when the Global Polio Eradication Initiative began to 1,940 in 2005 (data as of March 14, 2006). This eradication initiative, whose aim is to eliminate all cases due to the wild virus throughout the world, now has tools in place to rapidly stop polio transmission everywhere except Nigeria, where, as of June 2006, another 12 months will be required." (June, 2006)

Examples of Live Attenuated Viral Vaccines

- MMR - Sabin (Polio) - Yellow fever - Live attenuated influenza-derived intranasally (not currently recommended) - Varicella (chicken pox) (Varivax or Proquad) - Rotavirus-delivered orally

Malaria in 2015

- Malaria is a life-threatening disease caused by parasites that are transmitted to people through the bites of infected female mosquitoes. - About 3.2 billion people - almost half of the world's population - are at risk of malaria. Approximately 429,000 die each year. - Young children, pregnant women and non-immune travellers from malaria-free areas are particularly vulnerable to the disease when they become infected.

Malaria in 2015 (II)

- Malaria is preventable and curable, and increased efforts are dramatically reducing the malaria burden in many places. - Between 2000 and 2015, malaria incidence (the rate of new cases) fell by 37% globally. In that same period, malaria death rates fell by 60% globally among all age groups, and by 65% among children under 5. - Sub-Saharan Africa carries a disproportionately high share of the global malaria burden. In 2015, the region was home to 89% of malaria cases and 91% of malaria deaths.

Why Vaccinate Against Measles?

- Measles was declared eliminated from the United States in 2000 but continues to circulate in many regions of the world and can be imported into the US by travelers. - Measles vaccine is highly effective with 1 dose being 93% effective and 2 doses being 97% effective at preventing measles.

Vaccines

- Must induce clonal expansion in T and/or B cells - Induce formation of memory cells - Next encounter with antigen induces a secondary response which is faster, bigger better and thus prevents serious disease - Therefore, Adaptive Immunity is KEY

Outcome of Phase 3 Trial

- Results of the clinical trial yielded mixed results. - The best protection was among children aged five to 17 months who received three doses of the vaccine a month apart, plus a booster dose at 20 months. - In this group, cases of severe malaria were cut by a third over four years. - The effectiveness of the vaccine waned over time, making the booster shot essential. - Without a booster the vaccine did not cut the rate of severe malaria over the trial period. - Did not prove very effective in protecting young babies from severe malaria.

HPV Vaccine - Cervarix

- Specific for HPV 16 and 18 - HPV 16 and 18 cause about 70% of cervical cancers; each of the other oncogenic HPV types accounts for a small percentage of all cervical cancers - Approved for females only

Capsular Vaccines

- Streptococcus pneumoniae (Prevnar 13) - Neisseria meningitidis - Hemophilus influenzae a) Conjugated vaccine is effective in reducing incidence and severity of childhood meningitis and pneumonia

Toxoid Vaccines (II)

- Toxin Activity is destroyed (formalin) - Retains sufficient antigenic activity to protect against disease --> Tetanus, diphtheria

Bacterial Vaccines

- Whole bacteria - Toxins - Capsular polysaccharides

Live Attenuated Viral Vaccines (Process)

1) The pathogenic virus is isolated from a patient and grown in human cultured cells 2) The cultured virus is used to infect monkey cells 3) The virus acquires many mutations that allow it to grow well in monkey cells 4) The virus no longer grows well in human cells (it is now attenuated) and can be used as a vaccine.

Smallpox Eradication Program

1948: the World Health Organization (WHO) took over the health functions of the League of Nations, at a time when smallpox was still a threat in at least 90 countries. 1958: WHO adopted a resolution put forth by the Soviet Union to attempt global eradication 1966: a resolution sponsored by several countries -- including the United States and Soviet Union -- was adopted, and a specific goal set for wiping out smallpox within ten years. In 1966 44 countries were still reporting the disease Improved technology (needles that were easier to clean and use, for example) also made delivering the vaccine more efficient. Wars and political uprisings slowed progress October, 1977: The last naturally-occurring case of smallpox in the world was contracted in Merka Town, Somalia 1978: two cases reported in Birmingham, England, from smallpox virus escaped from a research lab. One of the patients died. The director of the laboratory committed suicide. These were smallpox's last victims. 1979: a global commission certified that smallpox had been eradicated 1980: certification was officially accepted by the 33rd World Health Assembly

Advantages/Disadvantages of Killed Viral Vaccines

Advantage: Safe, does not cause disease Disadvantage: - Must produce large amounts of the virus - Incomplete activation - No replicatoin of virus, therefore immunity may not be as "good"

Killed Bacterial Vaccines

Bordetella Pertussis: - When given with tetanus toxoid and diphtheria toxoid (DTaP), the presence of the Bordetella organism causes stronger immune responses to the toxoids-->bad rxns - Now an "acellular" Bordetella preparation is used --> Toxoid, filamentous hemagglutinin, pertactin, fimbrial antigen.

Why We Vaccinate

CDC recommends vaccinations to protect children against >14 infectious diseases including: - Measles, Mumps, Rubella - Varicella (chickenpox) - Hepatitis B - Diptheria, tetanus, pertussis (whooping cough) DTaP - Haemophilus influenza type B (Hib) - Polio (IPV) - Influenza (flu) - Pneumococcal polysaccharide disease - Human papilloma virus - Rotavirus - Hepatitis A - Meningococcal B

Disadvantages of Live Attenuated Viral Vaccine

Can cause disease in immunosuppressed or immunodeficient individuals - VAPP (vaccine associated paralytic polio): reason OPV is no longer recommended - Varicella: vaccine contraindicated in children treated with high dose corticosteroid, cancer, leukemia, lymphoma or non-HIV immunodeficiency - Rotavirus vaccine: precautions for altered immunocompetence. Reversion to wild type or pathogenic virus.

Vaccines Against Capsular Antigens

Capsules: - Contain strain and species-specific antigens (polysaccharides) - Also determine pathogenicity i.e. they block alternate pathway activation. - Aim of vaccine is to produce complement-fixing anti-capsular antibody - Antibody response is usually T-independent a) Babies dont make good T-independent immune responses making them particularly susceptible to infection by encapsulated bacteria b) Polysaccharide is usually conjugated to a carrier protein.

Capsular Vaccines: Conjugates

Conjugating the polysaccharides antigen to a protein carrier improves the vaccine. Why? - More chance of class switching from IgM to IgG - Higher antibody titers - Generation of memory - Longer lasting immunity - More effective in younger children - More effective in younger children.

Live Natural Viral Vaccines (II)

Edward Jenner discovered that immunization with the relatively innocuous cowpox conferred protection against the more deadly smallpox. This discovery led to the widespread adoption of vaccination and was a major stimulus for the study of the phenomenon of immunity. - Vaccinia or vaccination - Example of a live natural vaccine - Protects against small pox.

Newer Vaccines: HPV

Estimated 80% of sexually active women acquire HPV by age 50 A quadrivalent vaccine (types 6, 11, 16 and 18) licensed in September. 2006 - Females 9-26 - Prevents or reduces incidence of: a) HPV-induced cervical cancer b) Cervical precursor lesions (dysplasia) c) Vaginal and vulvar cancer precursor d) Anogenital warts

HPV Vaccine-Gardasil 4

Human papillomavirus (HPV) - Approximately 100 different types of HPV (High risk - types 16, 18; Low risk - types 6 and 11) Vaccine consists of surface antigen - The current HPV vaccine (Gardasil), licensed in June 2006 contains types 6, 11, 16, and 18 - Composed of virus-like particles (VLPs) prepared from recombinant L1 capsid protein of HPV. - In 2009, Gardasil was also recommended for boys

Polio Vaccine

IPV (inactivated, injection) - No risk of vaccine associated paralytic polio (VAPP), no mucosal immunity - Currently recommended in the US. OPV (Oral, attenuated) - 95% protection (life long) - Induces intestinal immunity - Herd immunity - Rarely: Vaccine Associated Paralytic Polio (VAPP) - Two polio vaccines have been available since 1961. The inactivated polio vaccine (IPV) was available first, administered via injection in 1955. A more convenient form, administered as liquid drops via the mouth, was developed in 1961. This oral polio vaccine (OPV) was recommended for use in the U.S. for almost 40 years, from 1963 until 1998. polio was eliminated from the United States in 1979 and from the Western Hemisphere in 1991.

Ebola and Passive Immunization

In late July, when it looked like Dr. Kent Brantly wasn't going to make it, a small news item escaped Liberia. It spoke of Brantly's treatment - not of the Ebola vaccine, Zmapp, which Brantly later got. But of a blood transfusion. He had "received a unit of blood from a 14-year-old boy who had survived Ebola because of Dr. Brantly's care," the missive said. Now months later, Brantly, who has since recovered from his battle with the virus, has passed on the favor. A 26-year-old Dallas nurse named Nina Pham, who contracted the illness while treating the United States' first Ebola patient, has received Brantly's blood.

Subunit Vaccines

Include only the antigens that best stimulate the immune system - In some cases, these vaccines use epitopes - the very specific parts of the antigen that antibodies or T-cells recognize and bind to. - Use of only the essential antigens decreases the chance of adverse rxns to the vaccine. May contain from 1 to 20 or more antigens - Identifying which antigens best stimulate the immune system may be time consuming process and ambiguous.

Passive Immunization

Injection of pre-formed antibodies - From recovered patients or from horses - Used in pre-antibiotic days - Used today when toxins are already circulating (tetanus, diptheria, snake bite) - VZIG (Varicella zoster Immunoglobulin) - Would this be effective in the case of ebola?

Live Natural Viral Vaccines (II)

Jenners strategy cannot be applied to most pathogenic viruses because there is no "safe" counterpart Most viral vaccines used today are: - Killed or inactivated - Live attenuated

Live Attenuated Viral Vaccines

Mutated so that it has reduced ability to grow in humans cells - No longer pathogenic in humans - Usually made by growing the pathogenic viruses in cells from a non-human host a) Select for variants that grow in the non-human host b) But less fit to grow in the human host.

Controversy: Vaccines and Autism (II)

Newer Studies: - No relationship between MMR and autism - Researchers in the UK studied the records of 498 children with autism born between 1979 and 1998 a) Percentage of children with autism who received MMR was the same as unaffected children in the same region who received the MMR

Vaccination and Eradication

Officially Eradicated --> Smallpox Candidates in the near future --> Polio

Live Natural Viral Vaccines

One of the first "vaccines" used material from dried pustules of people who got "mild" smallpox. - Variolation --> Widely used in the 18th century, sometimes successful, sometimes induced lethal smallpox

Adjuvants (III)

Purified protein vaccines induce poor immunity. - Improved by adjuvants a) substances that induce non-specific inflammation b) Adjuvants also cause soluble antigens to aggregate --> clear slower, increase phagocytosis

Malaria Vaccine 2015

RTS, S/AS01 - a malaria vaccine that has been developed through a partnership between GlaxoSmithKline Biologicals (GSK) and the PATH Malaria Vaccine Initiative (MVI) - The clinical testing of RTS,S/AS01 is at least 5-10 years ahead of other candidate malaria vaccines. - RTS,S/AS01 is a vaccine against Plasmodium falciparum, with no protection against P. vivax malaria.

HPV Vaccine-Gardasil 9

Specific for HPV Types 6, 11, 16, 18

Adjuvants (II)

Strong immune responses require some degree of inflammation - During infection - initiated by microbial products a) Activate macrophages --> increase expression of co-stimulators (if the adjuvant is microbial) b) Recruit inflammatory cells

Controversy: Vaccines and Autism

Study in 1998 linked autism to MMR vaccine - Small sample size (12 children) - Study suggested that vaccine caused bowl problems -> impaired nutrient absorption - Study retracted by 10 of 13 authors

Toxoid Vaccines

These vaccines are used when a bacterial toxin is the main cause of the illness. - Inactivate toxins by treating them with formalin. - Such "detoxified" toxins, called toxoids, are safe for use in vaccines. Vaccination with toxoid, results in production of protective antibodies that bind and neutralize the toxin.

Subunit Vaccines (II)

Usually an antigenic surface structure. - Induce neutralizing antibody - Prevent infection - Usually made be recombinant techniques - Ex = Hep. B vaccine; HPV vaccine (protects against 6,11,16 and 18; "helps" protect against genital warts, precancerous cervical lesions and cervical cancer)

Progress and Future Plans

Vaccine efficacy: - Over the full duration of the trial, vaccine efficacy against clinical malaria in infants was 27% in the group that received four doses of RTS,S (3 doses at 6, 10 and 14 weeks of age, and a fourth dose 18 months later); and 18% in the group that did not receive the fourth dose of the vaccine. In these infants, no significant efficacy was noted against severe malaria, with or without a fourth dose. - Among children aged 5-17 months who received four doses on a 0, 1, 2, 20 month schedule, vaccine efficacy against clinical malaria was 39% over the full duration of the trial. With a four-dose schedule, the overall efficacy against severe malaria among children in this age group was 31.5%, with reductions in severe anaemia, malaria hospitalizations and all-cause hospitalizations also seen. - NEXT STEP:GSK is planning Phase 4 studies with a total of 40,000 children to be vaccinated, with a primary objective of further evaluation of safety as part of the Risk Management Plan approved by EMA. The pilot implementation in each of the 3-5 settings is likely to involve 100,000-200,000 children (for a total of 400,000-800,000), in a staged manner.

Newer Vaccines: Zoster

Vaccine licensed in 2006 for use in people aged 60 and over (Zostavax) - Most effective at ages 60-69 - Vaccine prevents shingles in 50% of vaccinated individuals - Vaccine prevents post-herpetic neuralgia in 67% of vaccinated individuals Does not treat shingles or post-herpetic neuralgia

Live Attenuated Bacterial Vaccines

Very few. - BCG Mycobacterium bovis (bovine tuberculosis) for TB (Mycobacterium tuberculosis) a) Efficacy varies in different populations b) Not used in the USA - Salmonella a) Defective in enzyme necessary for LPS synthesis.

Killed Viral Vaccine

Viral particles are chemically treated (formalin) or heated or irradiated - Influenza vaccine: used for H1N1pdm09 like virus, H3N2-like virus - Rabies vaccine - Salk polio vaccine

Polio Eradication in 2015

Wild Polio Virus (WPV) transmission remains endemic in: - Afghanistan, Nigeria, and Pakistan - During 2013-2014, outbreaks resulting from importation of WPV from those three countries occurred in eight previously polio-free countries in three world territories, threatening the progress made to date in achieving polio eradication. In 2015, all three of the regional polio outbreaks in 2014 appear controlled and reported WPV cases has decreased worldwide. - No new cases have been detected in Nigeria since July 2014. - Transmission in Pakistan and Afghanistan continue in 2015 Polio eradication appears increasingly feasible in the near future - bolstered by possible elimination of endemic WPV transmission from Nigeria and interruption of all the 2013-2014 outbreaks.

Polio Eradication in 2012

World Polio Day, October 24: Polio eradication partners around the world are marking the first World Polio Day since India was removed from the list of countries with active transmission of wild poliovirus. This development opened up a historic opportunity to complete polio eradication in the remaining endemic countries, powered by the World Health Assembly declaration of an 'emergency for global public health' and implemented through national emergency programmes run by the governments of Afghanistan, Nigeria and Pakistan. Since World Polio Day last year, the number of new cases of polio has declined by 64% (from 489 at this time last year to 175 this year). Noting the report of the meeting in November 2011 of the Strategic Advisory Group of Experts on immunization at which it stated "unequivocally that the risk of failure to finish global polio eradication constitutes a programmatic emergency of global proportions for public health and is not acceptable under any circumstances"