48th annual meeting · 2018. 4. 3. · other potential vaccines… phrma. vaccines: a report of the...

7/19/2014

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48th Annual Meeting

Navigating the Oceans of Opportunity

Are there rough seas ahead?Immunization Update and Clinical Pearls

Lisa Clayville Martin, PharmD, CDEDirector, Healthy Living ProgramCenter for Living Well - Disney

Disclosure

I do not have a vested interest in or affiliation with any corporate organization offering financial support or grant monies for this continuing education activity, or any affiliation with an organization whose philosophy could potentially bias my presentation

Objectives

Discuss controversies surrounding currently available vaccines

Review current vaccine quality concerns

Discuss status of vaccines in the pipeline

Discuss clinical pearls with current vaccines

Importance of Vaccines

Disease Eradication

PhRMA. Vaccines: A Report of the Prevention and Treatment of Disease Through Vaccines, 2013 Report, 2013.

Disease Eradication…


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Vaccines Save Lives!!

Over 40,000 adults die annually from vaccine-preventable diseases Each year varicella causes ~4 million cases of chickenpox,

11,000 hospitalizations, and 100-150 deaths

3 out of 1,000 persons with measles in the US will die

If we stopped immunizing… 2.7 million people worldwide would die from measles

600 children would die and many others would suffer from deafness, seizures, and mental retardation from meningitis

CDC. “What would happen if we stopped vaccinations?” http://www.cdc.gov/vaccines/vac_gen/whatifstop.htm

Vaccines Protect Others Too

CDC. What would happen if we stopped vaccinations? http://www.cdc.gov/vaccines/vac-gen/what itstop.htm

Pharmacists Role in Immunizations

What is the pharmacist’s role?

Educator

Facilitator

Immunizer

1996 APhA House of Delegates, Nashville, TN. APhA. Pharmacy-Based Immunization Delivery, 2013. Am J Health-Syst Pharm 2003;60:1371-1377.

Are pharmacists persuasive?

↑ to 94% of people respond to a pharmacist’s recommendation to be vaccinated

People were 74% more likely to be vaccinated if prompted by their pharmacist than if not prompted

No other healthcare professional is as accessible

APhA. Pharmacy-Based Immunization Delivery. April 2013 version.

Vaccine Controversies

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Controversy # 1

Measles

MMWR 2013;62(36):741-3

12 children

GI referral Normal development followed

by loss of acquired skills (ex. language) and associated diarrhea and abdominal pain

Sx onset following MMR vaccine (8/12)

Measles infection (1/12)

OM infection (1/12)

Wakefield Study (1998)

Lancet 1998;351(9103):637-41

Ripped from the headlines…

Ripped from the headlines…

Timeline

1999FDA reviews the use of thimerosal in childhood

vaccines

2001IOM Immunization Safety Committee states that the evidence was inadequate

to accept or reject a relationship. Hypothesis is

plausible.

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Thimerosal Removal

Removed or reduced to trace levels in all vaccines recommended for children ≤ 6 yo except a few inactivated influenza vaccines

Vaccine Manufacturer Formulation Hg Content* Indicated Age

Afluria CSL Limited Multidose vial 0.01% ≥ 9 yr

FluLaval ID Biomedical Multidose vial < 0.01% ≥ 3 yr

Fluvirin NovartisMultidose vial

Single-dose syringe0.01%Trace

≥ 4 yr

Fluzone Sanofi pasteur Multidose vial 0.01% ≥ 6 mo

* 0.01% = 25 μg Hg/0.5 mL dose Trace = < 1 μg Hg/o.5 mL dose

MMWR 2013;62(RR07):1-43

Timeline

1999FDA reviews the use of thimerosal in childhood

vaccines

2001IOM Immunization Safety Committee states that the evidence was inadequate

to accept or reject a relationship. Hypothesis is

plausible.

2004IOM rejects hypothesis of casual relationship between thimerosalcontaining vaccines and autism.

2010CDC study does not support association

between prenatal and infant exposure to

thimerosal-containing vaccines and Ig and ↑ risk

of ASD.

Outbreaks

Disease 2006 2007 2008 2009 2010 2011 2012

Diphtheria 0 0 0 0 0 0 0

Hib 29 22 30 35 23 14 21

Measles 55 43 140 71 63 220 55

Mumps 6584 800 454 1991 2612 404 199

Pertussis 15632 10454 10007 16858 27550 18719 41880

Polio 0 1 0 0 0 0 0

Rubella 11 12 17 3 5 4 8

Tetanus 41 20 15 18 26 36 36

Varicella 32242 40146 30386 20480 15427 14513 11477

MMWR 2011;60(32):1089-1101. MMWR 2011;60(51):1762-75. MMWR 2014;62(51&52):1041-56.

Measles in 2014

www.cdc.gov/measles. Accessed April 28, 2014.

MMR Delay and Seizures

Self-controlled case series of 323,247 US children born 2004-2008

Result Delaying 1st MMR dose past 15 months of age

increased risk of seizures 12-15 mo (recommended) – IRR 2.65 (95%CI 1.99-3.55)

16-23 mo – IRR 6.53 (95% CI 3.15-13.53)

Pediactrics 2014;133:31492-9

Pertussis

CDC. ACIP Meeting Presentations Slides, June 19, 2013.

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Pertussis Recommendation

Adults Single Tdap dose to adults ≥ 19 years regardless of

interval since last tetanus or diphtheria-containing vaccine

Then continue Td for routine booster immunization every 10 years

MMWR 2006;55(RR-3):1-50. MMWR 2012;61(25):468-70.

Pertussis Recommendation

Pregnancy Single Tdap dose during each pregnancy irrespective of

prior Tdap history Administration at 27-36 weeks is optimal

3rd trimester produces highest concentration of antibodies transferred to fetus

If not administered during pregnancy, administer immediately postpartum

MMWR 2013;62(7):131-5

Controversy # 2

Childhood Vaccines

Year # vaccines # injections by 2 yo# injections at a

single visit

1900 1 1 1

1960 5 8 2

1980 7 5 2

2000 11 20 5

Pediatrics 2002;109:124-9

Neonatal Immune System

B and T cells are present by 14 weeks’ gestation

At birth Humoral and cellular immune responses functional IgM, IgG, and secretory and monomeric IgA

Helper T-cell (Th) Th1

Th2

Cytotoxic T-cell responses

B cells responses are deficient

Pediatrics 2002;109:124-9. Int Rev Immunol 2000;19:173-93. Vaccine 2001;19:3331-46.

Overwhelmed Immune System?

Circulating blood contains ~ 107 B-cells/mL

If each vaccine contained ~100 antigens and 10 epitopes per antigen

Each infant would have the theoretical capacity to respond to

10,000 vaccines at any one time…

Pediatrics 2002;109:124-9. Immunol Rev 1990;115:9-147.

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Childhood Vaccines

1900 1960 1980 2000

Vaccine Proteins Vaccine Proteins VaccineProtein

sVaccine Proteins

SmallpoxTOTAL

~200~200

SmallpoxDiphtheria

TetanusWC-Pertussis

PolioTOTAL

~20011

300015

~3217

DiphtheriaTetanus

WC-PertussisPolio

MeaslesMumpsRubellaTOTAL

11

~3000151095

~3041

DiphtheriaTetanus

AC-PertussisPolio

MeaslesMumpsRubella

HibVaricella

PneumococcalHepatitis B

TOTAL

11

2-515109526981

123-126


Simultaneous vs. Separated

Similar humoral immune responses were seen when given at the same or different times for MMR and varicella

MMR, DTP, and OPV

Hepatitis B, DT, and OPV

Influenza and pneumococcus

MMR, DTP-Hib, and varicella

MMR and Hib

DTP and Hib


Immune System Weakened?

Vaccines may cause a temporary suppression of delayed-type hypersensitivity skin reactions or alter certain lymphocyte function tests in vitro

Does not results in ↑ risk Germany study (n=496 children) Children who received DTP, Hib, and polio within first 3

months of life had fewer infections with vaccine-related and –unrelated pathogen than the unvaccinated group

Pediatrics 2002;109:124-9. J Infect 2000;41:172-5.

Vaccine Quality

VAERS

VAERS. http://vaers.hhs.gov/data/data Accessed May 9, 2014

VAERS Analysis

National Vaccine Information Center. www.medalerts.org/analysis/archives/628. Accessed May 9, 2014

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VAERS 2013

Total numbers (67 vaccine types) 43,456 reports

8,623 ER visits

1,335 hospitalizations

128 deaths

VAERS database – 2013. http://vaers.hhs.gov/data/data Accessed May 9, 2014

VAERS 2013

VAERS database – 2013. http://vaers.hhs.gov/data/data Accessed May 9, 2014

ISMP VERP

ISMP National Vaccine Errors Reporting Program Partner with the California Department of Public Health

Began in September 2012

1st report published in November 2013 433 total reports submitted

90% of errors reached the patient

6% were “close calls”

4% were hazardous conditions

ISMP. First Annual Review of Data Submitted to the ISMP VERP. http://www.ismp.org/Newsletters/acutecare/showarticle.aspx?id=64

ISMP VERP

Vaccine% of

ReportsTop Contributing Factor %

Influenza 18 Age-dependent formulations of same vaccine 37

DTaP-IPV 12 Not familiar with indicated patient ages for product 56

HepA 8 Age-dependent formulations of same vaccine 48

Tdap 8 Similar vaccine abbreviations 38

HPV4 5 Vaccine stored at temperatures lower than recommended 60

Hib 5 Patient age not verified before administration 25

DTaP 4 Age-dependent formulations of same vaccine 25

HepB 4 Similar vaccine container labels/packaging 22

Zoster 3 Not familiar with the route of administration 33

DTaP-HepB-IPV 3 Patient chart not checked before administration 33

MMRV 3 Not familiar with indicated patient ages for product 38

DTaP-IPV/Hib 3 Not familiar with how to mix or prepare product 40

ISMP. First Annual Review of Data Submitted to the ISMP VERP. http://www.ismp.org/Newsletters/acutecare/showarticle.aspx?id=64

Vaccine Recalls

Gardasil (Merck) 12/19/2013 Lot# J007354, distributed 8/20/13-10/9/13 Some vials may contain glass particles

Menveo (Novartis) 12/2/13 Lot# M12115 Higher than specified levels of residual moisture within the lyophilized

component

Recombivax HB (Merck) 6/26/13 Lot# J001183, distributed 3/12/13-5/2/13 Cracked vials

2013 Bilogics Recall. www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/Recalls/ucm343834.htm Accessed May 9, 2014

Vaccines in the Pipeline

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Vaccine Status


Applications Submitted

H5N1 pre-pandemic influenza A vaccine

Grass pollen extract sublingual vaccine

MK-3641 ragweed allergy vaccine

MK-7243 grass pollen allergy immunotherapy vaccine

Hepatitis B


HIV Hepatitis C C. diff Breast Cancer Anthrax Ovarian Cancer Smoking Cessation Lung Cancer Alzheimer’s Disease

Multiple Sclerosis Malaria Cholera Type 1 diabetes Traveler’s diarrhea Lymphoma Melanoma Norovirus Avian flu

Other Potential Vaccines…


Clinical Pearls

Clinical Pearl # 1

TOGETHER or SEPARATE…

CDC Recommendation

All vaccines can be administered at the same visit in separate locations

An inactivated and live vaccine can be administered either simultaneously or separately at any interval between doses

CDC. Immunizations: You Call the Shots. http://www2a.cdc.gov/nip/isd/ycts/mod1/courses/genrec/1000.asp?student_id. MMWR2011;60:1-61. CDC. Guidelines for spacing the administration of live and killed antigens. http://wonder.cdc.gov/wonder/prevguid/p0000348/p0000348.asp#Tanle6

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FDA Recommendation

2010 “Zostavax and Pneumovax 23 (pneumococcal vaccine)

should not be given concurrently because concomitant use resulted in reduced immunogenicity of Zostavax.”

2011 “In a randomized clinical study, a reduced immune response

to Zostavax as measured by gpELISA was observed in individuals who received concurrent administration of Pneumovax 23 and Zostavax compared with individuals who received these vaccines 4 weeks apart. Consider administration of the two vaccines separated by at least 4 weeks.”

FDA. MedWatch. Zostavax. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm200862.htm

MacIntyre, et al.

Non-inferiority randomized, double-blind, placebo-controlled study

N = 471

Zoster + PPV23

PPV23

Placebo Zoster

Day 1

Week 4

n = 235 n = 236

VZV antibodies checked on Day 1, Week 4, and Week 8Hum Vaccin 2010;6:894-902

MacIntyre, et al. Results

GMT ratio (concomitant vs. nonconcomitant) 0.70 (95% CI 0.61-0.80)

Did NOT meet noninferiority requirements However, between-group differences in antibody levels for

VZV (GMFR) and antibody levels for PnPs (GMT) werenoninferior

Concluded that Zostavax and PPV23 should NOTbe given together

Hum Vaccin 2010;6:894-902

Tseng, et al.

Retrospective cohort analysis to see if concomitant administration of PPV23 and Zostavax was associated with increased zoster incidence

N = 7179 N = 7187

Nonconcomitant

PPV23 given 365-30 days PRIOR to Zoster

Concomitant

PPV23 given on the same days as Zoster

Vaccine 2011;29:3628-32

Tseng, et al. Results

56 cases of Zoster occurred in concomitant group vs. 58 cases in the nonconcomitant group Hazard ratio 1.19 (95% CI 0.81-1.74)

Between-group cumulative risk was NOT statistically significant (p=0.76)

Concluded that simultaneous administration of PPV23 and Zostavax was NOT associated with an increased incidence of zoster

Hum Vaccin 2010;6:894-902

Clinical Pearl # 2

Am I too early or too late?

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Maximum Intervals

NO maximum intervals Exception: Oral typhoid vaccine (Ty21a) If extended > 3 weeks – repeat series

Immunologic memory

Until series is complete, person may remain susceptible to the associated VPD

MMWR 2011;60(2):1-60

Minimum Intervals

Insufficient time to mount an immune response Efficacy cannot be assured

Ideally use Recommended Intervals

Exceptions Catch-up schedule > 1 month behind

International travel

Potential loss to follow-up

MMWR 2011;60(2):1-60

Minimum Intervals

VaccineRecommended

Interval to Next DoseMinimum Interval

to Next Dose

Hepatitis B (HepB-1)HepB-2HepB-3

1-4 months2-17 months

----

4 weeks8 weeks

----

Diphtheria-tetanus-pertussis (DTaP-1)DTaP-2DTaP-3DTaP-4DTaP-5

2 months2 months

6-12 months3 years

----

4 weeks4 weeks6 months6 months

----

Haemophilus influenzae type b (Hib-1)Hib-2Hib-3Hib-4

2 months2 months

6-9 months----

4 weeks4 weeks8 weeks

----

Inactivated Poliovirus (IPV-1)IPV-2IPV-3IPV-4

2 months2-14 months3-5 years

----


----MMWR 2011;60(2):1-60

Minimum Intervals

VaccineRecommended


to Next Dose

Pneumococcal conjugate (PCV-1)PCV-2PCV-3PCV-4

8 weeks8 weeks6 months

----


----

Measles-mumps-rubella (MMR-1)MMR-2

3-5 years----

4 weeks----

Varicella (Var-1)Var-2

3-5 years----

12 weeks----

Hepatitis A (HepA-1)HepA-2

6-18 months----

6 months----

Meningococcal conjugate (MCV4-1)MCV4-2

4-5 years----

8 weeks----

Meningococcal polysaccharide (MPSV4-1)MPSV4-2

5 years----

5 years----

MMWR 2011;60(2):1-60

Minimum Intervals

VaccineRecommended


to Next Dose

Pneumococcal polysaccharide (PPSV-1)PPSV-2

5 years----

5 years----

Human papillomavirus (HPV-1)HPV-2HPV-3

2 months4 months

----

4 weeks12 weeks

----

Rotavirus (RV-1)RV-2RV-3

2 months2 months

----

4 weeks4 weeks

----

Other• Influenza (IIV/LAIV)• Tetanus-diphtheria (Td)• Tetanus-diphtheria-pertussis (Tdap)• Herpes zoster

1 month10 years

------

1 month5 years

--------

MMWR 2011;60(2):1-60

Grace Period

May give vaccine ≤ 4 days PRIOR to minimum interval

Should NOT be used To preschedule vaccine appointments

With live vaccines

Need to check with local and state health departments to see if they allow the grace period

MMWR 2011;60(2):1-60

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No Grace Period

MMR-1 “On or after 1st birthday” Helps to ensure effectiveness of live-virus vaccine is NOT

compromised by the potential presence of maternal antibodies

HepB and infants At least 4 weeks between HepB-1 and HepB-2 At least 8 weeks between HepB-2 and HepB-3 At least 16 weeks between HepB-1 and HepB-3

Rabies 4 doses (Day 0, 3, 7, 14) – previously unvaccinated 2 doses (Day 0, 3) – previously vaccinated

MMWR 2011;60(2):1-60

Clinical Pearl # 3

Altered Immunocompetence

Primary Generally inherited Absence or quantitative deficiency of cellular and/or humoral

components that provide immunity X-linked agammaglobulinemia Severe combined immunodeficiency disease Chronic granulomatous disease

Secondary Generally acquired Loss or qualitative deficiency in cellular/humoral immune components that

occurs as a result of a disease process or its therapy HIV Hematopoietic malignancies Radiation Treatment with immunosuppressive drugs

MMWR 2011;60(2):1-60

Immunosuppressive Drugs

Corticosteroids ≥ 20mg/day of prednisone (or equivalent) for a

person weighing > 10kg for ≥ 14 days

Does not include Alternate-day treatment with short-acting preparations

Topical, inhaled, or injection (intraarticular, bursal, tendon)

Low-dose therapies for chronic autoimmune diseases Therapeutic monoclonal antibody preparations TNF agents

MMWR 2011;60(2):1-60

General Principles

Vaccines might be less effective during altered immunocompetence Live vaccines should be deferred until immune function

has improved

Inactivated vaccines might need to be repeated once immune function has improved

Persons with altered immune competence might be at an increased risk for adverse reactions to live vaccines due to uninhibited replication

MMWR 2011;60(2):1-60

Indicated Vaccines

Some vaccines are indicated specifically for patients with altered immunocompetence due to demonstrated effectiveness or an increased risk for disease if vaccine withheld Pneumococcal vaccines (PCV and PPSV)

Influenza

Meninogococcal

Haemophilus influenzae type b

MMWR 2011;60(2):1-60

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Pneumococcal Vaccines

Immunocompromised Condition PCV13 PPSV23PPSV23

revaccination

Congenital/acquired immunodeficiency

HIV

Chronic renal failure

Nephrotic syndrome

Leukemia

Lymphoma

Hodgkin disease

Generalized malignancy

Iatrogenic immunosuppression*

Solid organ transplant

Multiple myeloma * Diseases requiring treatment with immunosuppressive drugs

MMWR 2012;61(40):816-9

Zoster

If immunosuppression is expected Vaccinate 14-30 days PRIOR to therapy if possibleOFF LABEL: transplant patients < 60 yr

If receiving immunosuppressive therapy Wait at least 1 month AFTER discontinuing high-dose

corticosteroids, isoantibodies, immune-mediators, immunomodulators

Wait at least 3 months AFTER discontinuing cancer chemotherapy

MMWR 2008;57(RR-5):1-64. Immunization Action Coalition. Ask the Experts: Zostavax, http://www.immunize.org/askexperts/experts_zos.asp. Accessed May 29, 2014.

Zoster

Patient receiving treatment for Rheumatoid Arthritis Psoriasis Polymyositis Sarcoidosis Inflammatory Bowel Syndrome

No contraindications for administration IF… Methotrexate (≤ 0.4 mg/kg/week) Azathioprine (≤ 3 mg/kg/day) 6-mercaptopurine (≤ 1.5 mg/kg/day)

MMWR 2008;57(RR-5):1-64

Zoster and Antivirals

Acyclovir, famciclovir, and valacyclovir may interfere with the zoster vaccine Discontinue medication at least 24 hours BEFORE

administration

Do NOT use for at least 14 days AFTER administration

MMWR 2008;57(RR-5):1-64

Clinical Pearl # 4

Potential Causes

Manufacturer NOT able to produce enough supply fast enough Changes in recommendation (ex. Tdap)

Manufacturer decides to stop producing the vaccine Single antigen Measles, Mumps, Rubella

Supplier can’t send out supply quick enough

http://www.familydoctor.org/familydoctor/en/kids/vaccines/vaccine-shortages.html. Accessed May 29, 2014.

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Potential Consequences

Triage and Prioritize Who is considered to be at greatest risk Elderly

Very young

Pregnant women

Persons with co-morbidities

Persons anticipating international travel

http://www.familydoctor.org/familydoctor/en/kids/vaccines/vaccine-shortages.html. Accessed May 29, 2014.

Current Shortages

Product Onset Date Current Status

Pentacel® (DTaP/Hib/IPV), Daptacel® (DTaP), Adacel® (Tdap)• Sanofi Pasteur Limited• Under supply limitations to help manage inventory• Production has increased beginning October 2013

April 2012 Ongoing

Black Widow Spider Antivenin• Merck• Limited to confirmed cases due to shortage of active ingredient

January 2009 Ongoing

TheraCys® (BCG Live)• Sanofi Pasteur Limited• Unavailable due to complying with Good Manufacturing Practices

May 2012 Ongoing

TiceBCG• Organon Teknika• May go on allocation if demand exceeds current increased

production plans and inventory

May 2012 Ongoing

RabAvert (Rabies)• Novartis Vaccines and Diagnostics• Limited supply – available through wholesaler/distributor channels

September 2011

Ongoing

CBER-Regulated Products: Current Shortages, Updated 5/19/14.

Resources

Helpful Sites

CDC http://www.cdc.gov/vaccines

Florida SHOTS https://www.flshots.com

Immunization Action Coalition http://www.immunize.org

48th annual meeting · 2018. 4. 3. · other potential vaccines… phrma. vaccines: a report of the...

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