Preventing Infections Adult Vaccines: Update 2017 Thomas M File, Jr MD MSc MACP FIDSA FCCP

Chair, Infectious Disease Division

Summa Health, Akron, Ohio;

Professor of Internal Medicine, Chair of Infectious

Disease Section, Master Teacher

Northeast Ohio Medical University,

Rootstown, Ohio

Review new developments in adult vaccines Focus on Influenza and pneumococcal

vaccines Additional comments: Zoster, Tdap, HPV,

Meningococcal B

Objectives

3 Vaccine evaluation center 2015

•Falling rates

•Success of past vaccines oLack of awareness of disease that is prevented

•Effects of anti-vacccine movement oFear, mistrust, ignorance

Threats to Vaccines

GA Poland 2011

Adult Immunization Coverage, US

MMWR. Feb 5, 2016. http://www.cdc.gov/mmwr/volumes/65/ss/ss6501a1.htm

Healthy People 2020 Objectives on Immunization and Infectious Disease. www.Healthypeople.gov/2020/.

**Influenza Estimates 2014-15.

Consequences of lapses of immunization: Outbreaks

•California (2010) •9,143 cases of pertussis (including ten infant deaths)

were reported throughout California. Most cases

reported in 63 years. •Measles outbreak source

•Ohio (2010-2014) oIn 2010, there were 964 cases of pertussis reported by

Columbus and Franklin Counties. Most cases reported

in 25 years. oIn 2014, there have been 377 cases of measles (10

hospitalized) since March. oIn 2014, there have been 460 cases of mumps (many

linked to OSU) since Jan.

Burden of Vaccine-Adult

Preventable Disease in the US

Disease Annual Burden of Disease, United States

Influenza 200,000 hospitalizations; 36,000 deaths (> 90% in older

adults)

Invasive

pneumococcal

disease

44,000 cases, 4500 deaths (higher rates of both in older

adults and persons with comorbidities)

Hepatitis B 51,000 infections (95% adults); 2000-3000 deaths;

1.25 million with chronic HBV infection

Human

papillomavirus

6.2 million new infections (>4000 women die in US

annually; ? Male deaths)

Pertussis

10,454 cases reported in 2007 (3152 adults)

Severe illness in infants; often transmitted by older child or

adult

Zoster 1 million cases; risk for shingles and postherpetic neuralgia

increases with age

It is September and you are evaluating a 65 year old male, smoker,

who has chronic lung and heart disease. Your nurse asks if he

would like to receive the influenza vaccine but he declines because

“last time I received the vaccine I developed the flu shortly

afterwards.” What is your most appropriate response?

A. B. C. D. E.

0% 0% 0%0%0%

A. Tell him all vaccines have life-threatening adverse effects

which are common.

B. In order to convince him, tell him there are no side effects of

the vaccine

C. Since you want him to feel satisfied with your patient-doctor

relationship, you pleasantly accept his response.

D. Strongly recommend the vaccine stating it cannot transmit

infection and the risk of disease is high in his case.

E. Tell him that if he refuses the vaccine you will no longer

participate in his care. 10

•Clear and unambiguous message to public, patients, providers o High benefit/risk ratio

o SAFE

•Low rates lead to outbreaks and death

•Anti-vaccine movement is harmful to public health

Need to improve Vaccine Uptake

GA Poland 2011

Physician-Patient

Miscommunication

National Foundation for Infecgious Diseases. Surveys of consumers and physicians 2010

The Communications Breakdown

“You need to get this

vaccine.”

OR

“I want you to get this

vaccine.”

Vaccine-Motivated

Patient

“Do you want this vaccine?”

OR

“Think about

getting the vaccine.”

Vaccine-Ambivalent

Patient

Recommendation

Not a Recommendation

Vaccines: Very high benefit/risk ratio

All vaccines have possible side effects, most mild, rarely severe

The risk of disease far outweighs the risk of vaccine

MESSAGE: Vaccines Effective Need Clear, Unambiguous message

Safe Need to recommend

2016/17 U.S. Influenza Vaccine Composition

oA/California/7/2009 (H1N1)

• Changed for 2017/18: A/Michigan/45/2015

o A/Hong Kong/2014)

oB/Brisbane/60/2008-like virus; Victoria

strain)

oB/Phuket/3073/2013-like virus

(Quadrivalent). • Similar to last year (Yamagata Strain)

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INFLUENZA VACCINE-Importance

oInfluenza may lead to many complications in adults • secondary pneumonia

• exacerbation of underlying disease(i.e., chronic lung or heart disease)

oHigh Risk patients: > 65; Chronic Conditions: Pulmonary

(including asthma), CV (except hypertension), Renal, Liver, Hematologic,

Neurologic, smokers; Immunosuppression (including HIV);

Residents of chronic care facilities; Pregnancy; Children

< 19 on aspirin; Obesity oInfluenza virus changes antigens over time; patients may therefore, not be immune because of prior exposure

oEfficacy • Depends on: 1. Immunogenicity; 2. Serotype match

• Recently varied 20-60% pending patient type

oCan be given at SAME time as pneumococcal vaccine

Influenza Vaccine – Abundant Choices for the Clinician

• IIV4, Standard Dose

o Fluarix (≥3 y.o.)

o Flulaval (≥3 y.o.)

o Fluzone (≥6 months)

• IIV4, Standard Dose, Intradermal

o Fluzone Intradermal (18-64 y.o.)

• ccIIV4, Standard Dose

o Flucelvax (≥4 y.o.)

• IIV3, Standard Dose

o Afluria (≥9 y.o.)

o Fluvirin (≥4 y.o.)

• aIIV3, Standard Dose

o Fluad (≥65 y.o.)

• IIV3, High Dose

o Fluzone High-Dose (≥65 y.o.)

• RIV3

o Flublok (≥18 y.o.)

• LAIV4**

o FluMist (2 to 49 y.o.)

*MMWR. 2016; 65(5):1-54. Fluarix and Flulaval (GlaxoSmithKline); Fluzone, Fluzone Intradermal, Fluzone High-Dose (Sanofi Pasteur); Flucelvax,

Afluria, Fluvirin, Fluad (Seqirus); Flublok (Protein Sciences); FluMist (MedImmune).

**Flumist, while approved by the FDA, is not CDC recommended or available on the market for the 2017-18 season.

IIV inactive influenza vacc; ccIIV cell culture IIV; aIIV adjuvanted IIV; RIV recombivant IIV

Case Exercise 1 Which vaccine for:

A 67-year-old man with type 2 diabetes mellitus and no history of egg allergy?

A. IIV3, standard

B. IIV3 high-dose (Fluzone High-Dose)

C. IIV4, intradermal (Fluzone Intradermal)

D. ccIIV4 (Flucelvax)

Influenza Vaccine Regular Dose

IIV3 or IIV4: ‘Killed’, injectable • 6 months and older– Trivalent (IIV3) or Quadrivalent (IIV4)

• FDA-indicated ages may vary by manufacturer:

‒ Practically speaking, these vaccines are for anyone who doesn’t have a contraindication to influenza vaccine

IIV4 Intradermal (Fluzone® Intradermal)

• FDA approval for 18-64 years

• Manufacturer-supplied injection device (includes needle)

‒ 90% smaller needle; 9 mcg of each antigen (compared to 15 mcg of standard dose in IIV4)

• Quadrivalent

IIV, Inactivated Influenza vaccine

Fluzone® Intradermal Quadrivalent (Influenza Vaccine) Prescribing Information. Sanofi Pasteur Inc., Swiftwater,

PA. June 2016.

Influenza Vaccine High Dose

IIV3, high-dose (Fluzone® High-Dose) • Contains 60 mcg each of the 3 influenza antigens

(compared to 15 mcg each for regular IIV3) oSlightly higher rate of MILD reactions

• Indications: Patients ≥65 years. • Clinical trial had shown high-dose vaccine was 24.2%

more effective in preventing influenza in adults ≥65 than the standard vaccine.

• NEW STUDY (CDC March 2017): High Dose associated with 38% reduction in mortality

Fluzone High-Dose (Influenza Vaccine) Prescribing Information. Sanofi Pasteur Inc. Swiftwater, PA.

June 2016.

1. DiazGranados CA, et al. N Engl J Med. 2014;371:635-45.; 2.

Influenza Vaccine Adjuvanted Vaccine

aIIV3, adjuvanted vaccine (Fluad) • Trivalent inactivated influenza vaccine plus a proprietary adjuvant that

is proposed to recruit immune cells at the site of injection and enhance antigen uptake

oResults in potentially greater immunogenic response in elderly patients

• Indication: Patients ≥65 years.

• Clinical trials show non-inferiority with IIV3 based on seroconversion and geometric mean titers

oNo data yet available that demonstrate decrease in influenza disease

Fluad™ (influenza vaccine, adjuvanted) Prescribing Information. Sequiris, Inc., Holly Springs, NC. March 2016.

Case Exercise 2 Which vaccine for:

A 19-year-old with history of severe allergic reaction (i.e., respiratory distress) to eggs?

A. IIV4, standard

B. aIIV3 (Fluad)

C. RIV3 (Flublok)

D. No vaccine/refer to specialist

Influenza Vaccine in Egg Allergies Cell-Cultured and Recombinant Vaccines

• ccIIV4 (Flucelvax® Quadrivalent) o In place of chicken eggs, uses animal cells (Canine Kidney) as host

(reference strain obtained from virus originally grown in eggs);

quadrivalent

o Approved for ages ≥4 years

• RIV3 (Flublok®) o Recombinant vaccine— egg-free hemagglutinin influenza vaccine

produced by recombinant DNA technology using a baculovirus (a virus

that infects insects) that produces virus-like particles, hemagglutinin

(vaccine of choice for true egg allergy)

o Approved for ages >18; only 16-week shelf-life; trivalent

• Adverse events similar to other inactive vaccines

Flucelvax® Quadrivalent (influenza vaccine) Prescribing Information. Sequiris, Inc., Holly Springs, NC. April 2016.

Flublok® (influenza vaccine) Prescribing Information. Protein Sciences Corp., Meriden, CT. September 2016.

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Influenza and Pregnancy

• Pregnant woman at high risk for severe complications and death o Cellular immune response diminished

• Maternal influenza associated with increased (Zaman et al. NEJM 2008) o Maternal hospitalization o Fetal malformation o Other illnesses

• Prevention is best approach • Newborns are at high risk for severe complications o Several reports of 2nd MRSA infection o No approved vaccine for infants < 6 months of age o All care givers need to be free from possible transmission

to this vulnerable population

Benefits/Obligations of Influenza

vaccine for Healthcare providers

• As HCW we all have an obligation to protect our patients o Transmission may occur without illness

• May be asymptomatic carriers • Infectious prior to onset of symptoms

o Studies show reduced transmission after vaccination

• Protection form acute illness oFor H1N1 greatest morbidity and mortality is in ‘healthy’

individuals aged 20-50.

• Protection of family members (especially if very young or with medical conditions)

• Mandatory immunization of all HCW being implemented at SUMMA

77% of Influenza ‘asymptomatic’

•Flu Watch Study1 oCourse of influenza over 5 cohorts (2006-11) oSerology; PCR; Weekly assessment for RTI

• Findings o77 % appeared to asymptomatic oOnly 17% of PCR-confrimed infection sought medical attention

• “A large number of well individuals in the community make a substantial contribution to transmission.”2

1. Hayward et al. Lancet Resp Med. 2014; 2: 445-54;

2. 2. Horby Lancet Resp Med. 2014; 2: 430

INFLUENZA VACCINE Reduction in Hospitalizations for Cardiac disease and

Strokes (Nichols et a. NEJM 348, April 3, 2003)

• Observational studies of large cohorts (140,000; 146,000), ’98-’99 AND ’99-’00, 3 HMOs, age 65

• Vaccination against influenza associated with reduction in hospitalization for : o Cardiac disease (19% both seasons) o Cerebrovascular disease (16%; 23%) o Pneumonia and Influenza (32%; 29%) o All cause Death (48%; 50%)

• Possible mechanisms: infection cause alterations in clotting factors, platelet aggregation, amount of inflammatory- response cytokines which enhance thrombosis

• Lower risk of Cardiovascular complications (JAMA. 2013;310(16):1711-1720)

Influenza ‘Nuts and Bolts’1

•Vaccination season: Soon as available to

~April o Influenza season unpredictable-can start Oct

o Immunity will last for almost all patients (no concern for

waning immunity for most))

oLate season vaccination important and underutilized

oLAIV can be safely used in MOST healthcare settings as

alternative to TIV2

•Egg allergy NO LONGER contraindication3

oAnaphylaxis is EXCEEDINGLY rare [<10 documented

cases]

oFlublok if concern

oOK to give egg-based if not history of severe anaphylaxis

• If vaccinated, should be observed ~30 minutes in office 1. Centers for Disease Control and Prevention. Inactivated Influenza Vaccine 2011-12. Available at: http://www.cdc.gov/vaccines/pubs/vis/downloads/vis-flu.pdf

2. Talbot TR, et al. Infect Control Hosp Epidemiol. 2010;31:987-995.

3. Kelso JM, Wang J. UpToDate. 2011. Available at: http://www.uptodate.com/contents/influenza-vaccination-in-individuals-with-egg-allergy.

Case Exercise 3

A 66-year-old man with COPD who has not received any immunization in the past 15 years. What do you recommend today?

A. Influenza vaccine

B. Pneumococcal vaccine

C. Zoster vaccine

D. A and B only

E. A, B, and C

Centers for Disease Control and Prevention. 2010. Active Bacterial Core Surveillance Report,

Emerging Infections Program Network, Streptococcus pneumoniae, 2009.

http://www.cdc.gov/abcs/reports-findings/survreports/spneu09.pdf. Accessed February 3, 2011.

Pneumococcal Diseases causes more deaths per

year in US than Breast Cancer or Prostate Cancer

Xu. Et al. Deaths: Prelimanary data for 2007. Natl Vital Stat Rep. 2009; 58: 1-51

Pneumococcal Vaccines-adults

• 90 known serotypes of S. pneumoniae

• Pneumococcal polysaccharide vaccine (PPSV23)

Inactive vaccine; contains 23 serotypes which account for majority (75-

80%) of clinical disease.

Approved for use in adults of any age; ? Efficacy for pneumonia

• Pneumococcal conjugate vaccine (PCV13) approved

for use in adults age 50 and older

Inactive vaccine, conjugated with diptheria CRM 197 protein); 13 serotypes

which account for approx 45-50% of invasive disease

Approval from FDA announced December 30, 2011 for adults 50 years and

older

Previously approved and recommended for use in children

CDC’s Advisory Committee on Immunization Practices (ACIP)

recommends use for patients who are immunocompromised

Strategies for sequential use of Conjugate and

Polysaccharide vaccine use in adults

• Conjugate vaccine more immunogenicity (higher antibody levels) and can have booster effect o 13 serogroups (accounts for approx 50% of invasive cases of

pneumococcal disease

• Polysaccharide vaccine less immunogenecity and NO booster effect (may have hyporesponsiveness) o But has 23 serogroups (accounts for approx 89% of invasive cases)

• Give Conjugate first followed by polysaccharide for potentially optimal effect

• If polysaccharide given initially wait one year to administer the conjugate vaccine (reduce ? Hyporesponsiveness)

34

35 Source: Designed by National Foundation for Infectious Disease based on CDC recommendations; 2012

CDC Recommendations 2015 for aged > 65

Which Vaccine(s)

24 year with asthma has not previously received any

pneumococcal vaccine

A. Conjugate 13

B. Conjugate 13 followed by Polysaccharide 23

one year later

C. Polysaccharide 23

D. Pneumococcal vaccine not indicated

Which Vaccine(s)

24 year with asthma has not previously received any

pneumococcal vaccine

PPSV23 now; PCV age 65 followed by PPSV 6-12 months

later

Which Vaccine(s)

28 year old woman with HIV infection received

one dose PPSV23 a year ago.

A. Conjugate 13

B. Conjugate 13 followed by Polysaccharide 23

one year later

C. Conjugate 13 followed by Polysaccharide 23

4 years later

D. Polysaccharide 23

Patient Scenario

28 year old woman with HIV infection received one

dose PPSV23 a year ago.

One dose PCV now (> one year since PPSV); 2nd dose

PPSV23 age 32 (> 5 years since PCV); 3rd dose PPSV age 65

Which Vaccine(s)

66 year old male, CHF, received PPSV23 age 55

A. Conjugate 13

B. Conjugate 13 followed by Polysaccharide 23

one year later

C. Conjugate 13 followed by Polysaccharide 23

4 years later

D. Polysaccharide 23

Patient Scenarios

66 year old male received PPSV23 age 55

One dose PCV13 now followed by PPSV 23 in one year

Another one:

68 year old who received PPSV23 age 66???

ACIP Tdap Recommendations

Specific Priority Groups

•Pregnant women at 27-36 weeks' gestation

oAT EACH PREGNANCY!

•Adults, regardless of age, who are in close contact with infants younger than age 12 months (e.g., parents, grandparents, or child-care providers)

•Healthcare Providers

Zoster Vaccine (Zostavax ™)

oLive vaccine

• Not for pregnancy, immunocompromised

oApproved for the prevention of herpes zoster

(shingles) in persons aged 50 years and older.

(CDC ≥ 60)

oSingle SC injection within 30 minutes of

reconstitution • In 38,000 patient study, reduced the incidence of shingles by 51% in persons aged 60 years and older (less effective in older patients)

• Incidence of postherpetic neuralgia less by 39%.

Zoster Vaccine (Zostavax ™)

Most common questions

oWhat if no history of chicken pox? • OK to give oWhat if past zoster? • Give after resolution of past episode; no specific time interval recommended

oIs it covered by Medicare •Covered by Part D not Part B. Insurance payment varies by plan.

•To be covered by ACA oShould I receive if around pregnant or immunosuppressed persons? •YES--not transmitted

Zoster: Special Consideration

• Simultaneous administration of pneumococcal vaccine o One study showed the average titer against varicella zoster virus (VZV)

was lower in persons who received zoster and PPSV at the same visit compared to persons who received these vaccines 4 weeks apart

o However, a large study was subsequently conducted that showed that zoster vaccine was equally effective at preventing herpes zoster whether it was administered simultaneously with PPSV or 4 weeks earlier

o CDC continues to recommend that HZV and PPSV be administered at the same visit if the person is eligible for both vaccines.

www.cdc.gov/vaccines/vpd-vac/shingles/hcp-

vaccination.htm&ei=LkhCVdGNM47SoAT46oGQAg&usg=AFQjCNFngsWk1AJGJ7j82iBjA-

2GCnYATw&bvm=bv.92189499,d.cGU (Mar 12, 2015)

NEW Zoster vaccine (Shingrix™): subunit recombinant, adjuvant

• Recombinant: VZV glycoprotein E (target of both humoral and cellular immune responses) with novel adjuvant

• High and sustained efficacy in clinical trials o ZOE-50: associated with a risk of herpes zoster that was 97.2% lower

than that associated with placebo in age 50 and older.1

o 2nd trial (ZOE-70) for 70 + demonstrated 89% efficacy and reduced PHN.2

o Pooled analysis: 91% efficacy against zoster; 89% against PHN

• 2 doses; AEs comparable.

• Recommended unanimously by ACIP advisory committee (approved by CDC 10/20/2017)

1. Lal H, et al. N Engl J Med. 2015;372:2087-2096.

2. Cunningham AL, et al. N Engl J Med. 2016;375:1019-1032.Mar 12, 2015)

HPV Vaccine

• HPV 9-valent vaccine (Gardasil 9, Merck)

• The vaccine is indicated for females aged 9 to 26

years and males aged 9 to 21 (22-26 high risk) years,

and for cancers caused by HPV types 6,11, 16, 18, 31,

33, 45, 52 and 58 and for the prevention of genital

warts caused by HPV type

• 97% effective in preventing cervical, vulvar and vaginal

cancers

• Last year CDC recommended reducing to 2 doses

• No apparent adverse effect if inadvertently given in

pregnancy (Quad; Scheller et al. NEJM 2017; 376:1223)

•Group B not in the Quadrivalent (A,C,Y,W) •High-risk individuals oComplement deficiencies, oanatomic or functional asplenia, omicrobiologists routinely exposed to N. meningitidis isolates

o serogroup B meningococcal disease outbreak •2 Vaccines: oTrumenba™ • 3 doses for high-risk; 2 doses* (6 months apart) healthy

oBexsero™: • 2 doses series

Meningococcal Serogroup B Vaccines

* ACIP Oct 2016

A. Pneumococcal

B. Hemophilus influenzae B

C. Meningococcal quadrivalent

D.Menigococcal B

E. All above

28 y/o male had splenectomy after MVA. Which vaccines should be administered after the splenectomy?

06.01.2016 Summa Health Sample Preso 50

51

A. Pneumococcal

A. PCV13; then PPSV23 > 8 weeks; PPSV23 in 5 years and at age 65

B. Hemophilus influenzae type B (Hib)

A. If not previously received

C. Meningococcal quadrivalent (ACWY)

A. Menveo™ or Menactra™ (2 doses each, 2 months apart)

D.Meningococcal B

E. All above

28 y/o male had splenectomy after MVA. Which vaccines should be administered after the splenectomy?

06.01.2016 Summa Health Sample Preso 52

The wars of the world: Saving lives

through vaccination

• Without the safe and effective vaccines that we too

often take for granted now, more than 300 million

who lived full and rewarding lives during the 20th

century would have died prematurely of a vaccine-

preventable disease. Compare this with the 160

million estimated to have been killed in all wars

combined during the same century. Stated another

way, vaccines saved twice as many lives as were lost

in war during the most destructive 100 years in

human history.

DW Kimberlin Inf Dis News. Aug 1, 2011