Pneumococcal Vaccine

Number: 0037

Policy

Aetna considers standard 23-valent pneumococcal polysaccharide vaccine (PPSV23), and pneumococcal 13-valent conjugate (PCV13) vaccines medically necessary according to the recommendations of the Centers for Disease Control and Prevention’s (CDC) Advisory Committee on Immunization Practices (ACIP).

Standard Pneumococcal Vaccine

Aetna considers standard 23-valent pneumococcal polysaccharide vaccine (PPV23, e.g., Pneumovax, Pnu-immune) medically necessary for all individuals aged 65 years or older.

Aetna considers standard pneumococcal vaccine medically necessary for persons over 2 years of age with any of the following conditions:

1. Acquired or congenital immunodeficiency (including HIV infection) 
2. Adults aged 19 through 64 years who have asthma
3. Adults aged 19 through 64 years who smoke cigarettes
4. After heptavalent pneumococcal conjugate vaccine (PCV7) in Alaska Native or American Indian children aged 24 through 59 months who are living in areas where the risk of invasive pneumococcal disease is increased
5. Alaska Native and American Indian persons aged 50 to 64 years who are living in areas where the risk of invasive pneumococcal disease is increased, when recommended by public health authorities
6. Alcoholism (6 years of age and older)
7. Asplenia (functional or anatomic)
8. Cerebrospinal fluid leaks
9. Children 2 through 18 years with asthma if treated with high-dose oral corticosteroid therapy
10. Chronic cardiovascular disease
11. Chronic liver disease (including cirrhosis) 
12. Chronic pulmonary disease
13. Chronic renal failure or nephrotic syndrome
14. Diabetes mellitus
15. Metastatic or hematologic malignancies
16. Multiple myeloma
17. Other conditions associated with immunosuppression (such as organ transplantation, bone marrow transplantation, and persons on immunosuppressive radiation or chemotherapy (including corticosteroids))
18. Persons living in special environments or social settings with an identified increased risk of pneumococcal disease 
19. Persons who have or are planning to receive a cochlear implant (see CPB 0013 - Cochlear Implants and Auditory Brainstem Implants)
20. Persons who will be undergoing elective splenectomy (vaccine should be administered at least 14 days prior to surgery; if it is not possible to administer the vaccine prior to splenectomy, it can be given after the 14th post-operative day)
21. Sickle cell disease.

Aetna considers standard pneumococcal vaccine experimental and investigational for other indications because its effectiveness for indications other than the ones listed above has not been established.

Routine re-vaccination is not recommended by the CDC.  In accordance with the CDC’s recommendations, Aetna considers re-vaccination medically necessary only for the following groups:

• Persons aged 65 years or older if they received vaccine 5 or more years previously and was less than 65 years of age at the time of vaccination
• Persons aged 2 to 64 years with the following conditions in which the second dose of PPSV23 is given at least 5 years after the first dose of PPSV23:
  
  
  • Anatomic or functional asplenia
  • Chronic renal failure or nephrotic syndrome
  • Congenital or acquired immunodeficiency (including HIV infection)
  • Generalized and metastatic malignancies
  • Hodgkin disease
  • Iatrogenic immunosuppression, including radiation therapy
  • Leukemia or lymphoma
  • Multiple myeloma
  • Sickle cell disease or other hemoglobinopathies
  • Solid organ transplant
  • Sickle cell disease or other hemoglobinopathies.

In addition, re-vaccination with the 23-valent pneumococcal polysaccharide vaccine is considered medically necessary for high-risk individuals who received the 14-valent polysaccharide vaccine, which was in use prior to 1983.

Re-vaccination has no proven value for other groups.

Pneumococcal 13-valent Conjugate Vaccine (PCV13, Prevnar 13)

Note: In 2010, heptavalent pneumococcal conjugate vaccine (PCV7, e.g., Prevnar, Prevenar) was replaced by PCV13 (e.g., Prevnar 13).

According to the recommendations of the CDC’s Advisory Committee on Immunization Practices, Aetna considers pneumococcal 13-valent conjugate vaccine (PCV13, Prevnar 13) medically necessary for all of the following:

• Children 2 through 59 months of age
• Children 2 through 5 years of age with the following medical conditions:
  
  
  • Chronic heart disease
  • Chronic lung disease, including asthma if treated with high-dose oral corticosteroid therapy
  • Diabetes mellitus
    
    
• Persons 2 through 64 years of age with the following medical conditions:
  
  
  • Anatomic or functional asplenia
  • Cerebrospinal fluid leaks
  • Chronic renal failure or nephrotic syndrome
  • Cochlear implant(s) (see CPB 0013 - Cochlear Implants and Auditory Brainstem Implants
  • Congenital or acquired immunodeficiency (including HIV infection)
  • Generalized and metastatic malignancies
  • Hodgkin disease
  • Iatrogenic immunosuppression, including radiation therapy
  • Leukemia or lymphoma
  • Multiple myeloma
  • Sickle cell disease or other hemoglobinopathies
  • Solid organ transplant

Aetna considers use of 13-valent pneumococcal conjugate vaccine (PCV 13; Prevnar 13) in series with PPSV23 (e.g. Pneumovax) medically necessary for adults aged 19 years or older (including those aged 65 years and older) with immunocompromising conditions, CSF leaks, or cochlear implants.

Aetna considers use of a dose of PCV13 (e.g., Prevnar 13) followed by a dose of PPSV23 (e.g., Pneumovax) medically necessary for adults aged 65 years and older who want to receive PCV13 and do not have an immunocompromising condition, cerebrospinal fluid leak, or cochlear implant and have not previously received PCV13. Note: if member already received PPSV23, a dose of PCV13 may be given at least one year after they received the most recent dose.

Aetna considers pneumococcal 13-valent conjugate vaccine (PCV13) experimental and investigational for other groups because its effectiveness for groups other than the ones listed above has not been established.

Background

This policy is based on the recommendations of the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices (CDC/ACIP), the U.S. Preventive Services Task Force (USPSTF), the American Academy of Pediatrics (AAP) Committee on Infectious Diseases, the American College of Physicians Task Force on Adult Immunization, and the Infectious Diseases Society of America.

Pneumococcal disease is an infection with the bacteria Streptococcus pneumoniae, which causes pneumonia, bacteremia, and meningitis.  Pneumococcal disease is a significant cause of morbidity and mortality in the United States.  Population-based surveillance studies have reported annual invasive pneumococcal disease rates of at least 15 to 19/100,000 population and pneumococcal meningitis rates of 0.3 to 1.2/100,000.  Significantly higher incidence rates are reported for persons less than 5 years of age or over age 65; African Americans, Native Americans, and Alaska Natives; nursing home residents; alcoholics; and those with chronic medical or immunodeficient conditions.

Pneumococcal disease accounts for about 15 % of severe community-acquired pneumonia, which has a case-fatality rate (proportion of cases resulting in death) of 9 to 26 %.  Pneumococcal bacteremia and meningitis are also associated with high case-fatality rates.  The highest case-fatality rates from invasive pneumococcal infection occur in elderly persons (30 to 43 %) and patients with co-morbid conditions (25 to 27 %).

Standard pneumococcal vaccine

Standard (unconjugated) pneumococcal polysaccharide vaccine (Pneumovax, Pnu-Immune) contains 23 purified capsular polysaccharide antigens of S. pneumoniae, and is protective against 88 % of the strains of S. pneumoniae causing bacteremic pneumococcal disease reported in the United States.  The 6 serotypes that most frequently cause invasive drug-resistant pneumococcal infection in the United States are represented in the 23-valent vaccine.  These vaccines were licensed in the United States in 1983 and replaced an earlier 14-valent formulation that was licensed in 1977.

Clinical studies have demonstrated the effectiveness of standard pneumococcal vaccine in reducing the incidence of pneumococcal pneumonia in the elderly and in immunocompetent high-risk groups.  A meta-analysis combining the most recent trials reported that vaccinated individuals had 11 fewer episodes of definitive pneumococcal pneumonia and 25 fewer episodes of presumptive pneumococcal pneumonia per 1,000 subjects (Fine, 1994).  Case-control studies and indirect cohort studies support the protective value of vaccine in immunocompetent recipients, with vaccine efficacy estimates of 60 to 75 % reported, but not in severely or relatively immunocompromised individuals, including those with alcoholism, chronic renal failure, immunoglobulin deficiency, nephrotic syndrome, sickle cell disease, multiple myeloma, metastatic or hematologic malignancies, or systemic lupus erythematosus.  For some of these disorders, efficacy point estimates suggest a benefit but the confidence intervals (CIs) are wide and include the possibility of no benefit.

The U.S. Preventive Services Task Force concluded that there is insufficient evidence to recommend for or against pneumococcal vaccine as an efficacious vaccine for immunocompromised individuals, but noted that recommendations for vaccinating these persons may be made on other grounds, including high incidence and case-fatality rates of pneumococcal disease and minimal adverse effects from vaccine.

Immunocompromised conditions associated with high risk for pneumococcal disease include alcoholism, cirrhosis, chronic renal failure, nephrotic syndrome, sickle cell disease, multiple myeloma, metastatic or hematologic malignancies, acquired or congenital immunodeficiencies (including HIV infection), and other conditions associated with immunosuppression, such as organ transplant.

For most individuals, accepted guidelines suggest a single vaccination is sufficient.  The CDC and UPSPTF do not recommend routine revaccination, but state that it may be appropriate to consider revaccination in certain immunocompetent individuals at highest risk for morbidity and mortality from pneumococcal disease who were vaccinated more than 5 years previously.  These authorities also state that it may be appropriate to consider periodic re-vaccination of certain high-risk immunocompromised patients, who are likely to have poor initial antibody response and rapid decline of antibodies after vaccination.  In addition, re-vaccination with the 23-valent pneumococcal polysaccharide vaccine may be appropriate for high-risk individuals who received the 14-valent polysaccharide vaccine, which was in use prior to 1983.

Standard pneumococcal vaccine may be given with other vaccines.  No data indicate that administration of pneumococcal vaccine with DTP, poliovirus, influenza, or other vaccines increases the severity of reactions or diminishes the responses.

Standard pneumococcal vaccine is not indicated in the prophylaxis of otitis media in children.  The safety of pneumococcal vaccine in pregnancy has not been evaluated.

There is insufficient evidence that pneumococcal vaccine effects the course of bronchiectasis.  In a Cochrane review, Chang and colleagues (2007) assessed the effectiveness of pneumococcal vaccine as routine management in children and adults with bronchiectasis in reducing the severity and frequency of respiratory exacerbations and pulmonary decline.  The authors concluded that currently there is a lack of reliable evidence to support or refute the routine use of pneumococcal vaccine as routine management in children and adults with bronchiectasis.  Randomized controlled studies examining the effectiveness of this intervention using various vaccine types in different age groups are needed.

The Pneumovax 23 vaccine is indicated for active immunization for the prevention of pneumococcal disease caused by the 23 serotypes contained in the vaccine (1, 2, 3, 4, 5, 6B, 7F, 8, 9 N, 9 V, 1 0 A, 1 1 A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F, and 33F). The FDA-approved indications for Penumovax 23 include use in persons 50 years of age or older and persons aged ≥ 2 years who are at increased risk for pneumococcal disease (Merck, 2019).

The ACIP recommendations for PPSV23 include the following (CDC, 2019):

• Persons 2 to 64 years of age with the following medical condtions:
  
  
  • Anatomic or functional asplenia
  • Cerebrospinal fluid leaks
  • Chronic heart disease
  • Chronic lung disease, including asthma (for 2 to 18 years of age if treated with high-dose oral corticosteroid therapy)
  • Chronic renal failure or nephrotic syndrome
  • Cochlear implant(s)
  • Congenital or acquired immunodeficiency
  • Diabetes mellitus
  • Generalized and metastatic malignancies
  • HIV infection
  • Hodgkin disease
  • Iatrogenic immunosuppression, including radiation therapy
  • Leukemia or lymphoma
  • Multiple myeloma
  • Sickle cell disease or other hemoglobinopathies
  • Solid organ transplant
    
    
• Persons 6 to 64 years of age with any of the following conditions:
  
  
  • Alcoholism
  • Chronic liver disease
    
    
• Persons 18 to 64 years of age
  
  
  • Cigarette smoking 

Adults Aged 65 Years and Older

A randomized placebo-controlled trial of 13-valent pneumococcal conjugate vaccine was conducted in about 84,500 adults aged 65 years and older, with no particular risk factors.  Four years on average after vaccination, there was no reduction in either mortality or the overall incidence of community-acquired pneumonia.  It was necessary to vaccinate about 1,000 individuals in order to prevent 1 case of vaccine-type pneumococcal pneumonia during the 4-year follow-up period (No authors listed, 2016).

In 2019, the Centers for Disease Control and Prevention (CDC) updated the recommendations of the Advisory Committee on Immunization Practices for use of 13-valent pneumococcal conjugate vaccine (PCV13). PCV13 vaccination is no longer routinely recommended for all adults aged 65 years and older. Instead, shared clinical decision-making for PCV13 use is recommended for persons in this age group who do not have an immunocompromising condition, CSF leak, or cochlear implant and who have not previously received PCV13. If a decision to administer PCV13 is made, it should be administered before PPSV23. The recommended intervals between pneumococcal vaccines remain unchanged for adults without an immunocompromising condition, CSF leak, or cochlear implant (≥1 year between pneumococcal vaccines, regardless of the order in which they were received). PCV13 and PPSV23 should not be co-administered. ACIP continues to recommend PCV13 in series with PPSV23 for adults aged ≥19 years (including those aged ≥65 years) with immunocompromising conditions, CSF leaks, or cochlear implants (Matanock et al., 2019).

All adults 65 years or older should receive 1 dose of PPSV23. Anyone who received any doses of PPSV23 before age 65 should receive 1 final dose of the vaccine at age 65 or older. Administer this last dose at least 5 years after the prior PPSV23 dose (CDC, 2019; Matanock et al., 2019).

Heptavalent pneumococcal conjugate vaccine

A 7-valent pneumococcal conjugate vaccine (Prevnar^TM, Prevenar^TM ) has been introduced by Wyeth Lederle for use in children.  The FDA has approved of this protein-polysaccharide conjugate vaccine for prevention of invasive pneumococcal disease (meningitis and bacteremia) in infants and toddlers.

The American Academy of Pediatrics and the CDC's ACIP recommended pneumococcal polyvalent vaccine for routine use in all children 2 and under, and for black, Alaskan Native, and Native American toddlers up to age 5, as well as for those with sickle-cell anemia, HIV infection, or other immunodeficiency diseases.  For infants, the AAP and ACIP recommends that the vaccine be given in 4 doses at 2, 4, 6, and 12 to 15 months; for children who are 7 to 11 months, 3 doses; for children who are 12 to 23 months, 2 doses; and for children 2 years or older, only 1 dose is needed.  See table below.

Table: Numbers of doses of Prevnar recommended by the ACIP for average risk children in each age range

Age range (months)	Number of doses
0 to 6	4
7 to 11	3
12 to 23	2
24 to 59	1

Pneumococcus is the most frequent cause of otitis media, pneumonia, and bacteremia in children, as well as the principle cause of childhood bacterial meningitis.  The most susceptible to pneumococcal diseases are children less than 2 years old.  Standard pneumococcal polysaccharide vaccines are poorly immunogenic in this age group.  The new protein-polysaccharide conjugate vaccine is immunogenic during infancy and is capable of providing long-term immunity.

Pneumococcal conjugate vaccine targets the seven serotypes (strains) of Streptococcus pneumonia that are responsible for 85 % of bacterial pneumonia in children.  The serotypes contained in the vaccine are also commonly associated with antibiotic resistance.

There is reliable evidence of the effectiveness of pneumococcal conjugate vaccine.  A 3-year, multi-center clinical trial involving 37,868 children reported that the pneumococcal conjugate vaccine was effective against invasive pneumococcal disease caused by seven prevalent serotypes of bacteria.  Pneumococcal conjugate vaccine had an efficacy rate of 97 % against invasive pneumococcal disease with vaccine serotypes, and a 93 % efficacy rate for disease with any serotype.  Children who received the pneumococcal vaccine were 1/3 less likely to develop x-ray confirmed pneumonia compared to children who received a conjugate meningococcal vaccine as a control.  Children who received the vaccine were 73 % less likely to have had severe pneumonia, and 89 % less likely to develop pneumococcal meningitis and bacteremia.  The results also suggested efficacy against frequent, recurrent otitis media; vaccinated children were 20 % less likely to have otitis media severe enough to require drainage tubes.

Although preliminary evidence indicates that pneumococcal conjugate vaccine may be safely administered with other childhood vaccines, the ACIP has recommended that further studies be performed on the safety of vaccine co-administration.

The FDA cautions that the pneumococcal conjugate vaccine is not indicated for use in adults.

A phase III trial evaluating the efficacy of the pneumococcal conjugate vaccine against pneumococcal otitis media is ongoing in Finland.  Wyeth Lederle is planning a supplemental filing for the otitis media indication.

The ACIP recommends pneumococcal vaccination for persons who have or are scheduled to receive a cochlear implant.  The ACIP recommends that children with cochlear implants aged less than 24 months should receive 7-valent pneumococcal conjugate vaccine, as is universally recommended; children with a lapse in vaccination should be vaccinated according to the catch-up schedule.  The ACIP recommends that children aged 24 to 59 months with cochlear implants who have not received pneumococcal conjugate vaccine should be vaccinated according to the high-risk schedule; children with a lapse in vaccination should be vaccinated according to the catch-up schedule for persons at high risk.  Children who have completed the 7- valent pneumococcal conjugate vaccine series should receive standard 23-valent pneumococcal vaccine more than 2 months after vaccination with 7- valent pneumococcal vaccine.  Persons aged 5 to 64 years with cochlear implants should receive standard 23-valent pneumococcal vaccine according to the schedule used for persons with chronic illnesses; a single dose is indicated.  The ACIP advises that persons planning to receive a cochlear implant should be up-to-date on age-appropriate pneumococcal vaccination more than 2 weeks before surgery, if possible.

In 2010, penumococcal 13-valen conjugate vaccine (PCV13) replaced 7-valent pneumococcal conjugate vaccine (PCV7) (CDC, 2019).

Pneumococcal 13-valent Conjugate Vaccine (PCV13, Prevnar 13)

The CDC's ACIP voted on February 24, 2010 to recommend the use of a 13-valent pneumococcal conjugate vaccine (PCV13, Prevnar 13) (Wyeth Pharmaceuticals Inc.), which provides broader protection for young children against pneumococcal diseases.  The vote came after the FDA had approved the vaccine for active immunization of infants and children aged 6 weeks through 5 years (prior to the 6th birthday) against Streptococcus pneumonia, which causes invasive pneumococcal diseases, such as pneumonia and meningitis, and against otitis media.  The new version of the vaccine protects against 6 more serotypes of Streptococcus pneumonia than the original version and is intended to replace PCV7.  Unlike PCV7, PCV13 includes serotype 19A, which is the most common serotype causing invasive pneumococcal infections in children.  In addition to serotype 19A, PCV13 also contains conjugated antigens representing serotypes 1, 3, 4, 5, 6A and B, 7F, 9V, 14, 18C, 19F, and 23F.

The FDA approval on February 24, 2010 was based on data from a clinical trial program including 13 core Phase 3 studies involving more than 7,000 infants and young children that showed the new 13-valent vaccine elicited immune responses comparable to that achieved with the 7-valent PCV.  FDA 2010 product information identified a 4-dose infant/toddler schedule to be administered at ages 2 months, 4 months, 6 months, and 12 to 15 months.

Adverse events were similar for both vaccines and most commonly included injection site reactions (pain, erythema, and inflammation), as well as irritability, decreased appetite, and fever.

The CDC's ACIP approved the following recommendations:

• Un-vaccinated infants and children: PCV13 is recommended for all children aged 2 through 59 months.  In the United States, infants receive a "3 plus 1" dosing schedule, with doses at 2, 4, and 6 months and a booster dose at 12 to 15 months.  Older children will follow the schedule currently recommended for PCV7.
• Children incompletely vaccinated with PCV7: Children aged 24 to 59 months who received 1 or more doses of PCV7 should complete their vaccine series with PCV13.  The age may be extended to 71 months for high-risk children (e.g., sickle cell disease, human immunodeficiency virus (HIV) infection or other immunocompromising conditions, cochlear implant, or cerebrospinal fluid leaks).
• Children completely vaccinated with PCV7: Children aged 14 to 59 months who have received all 4 doses of PCV7 should receive a single supplemental dose of PCV13.  The age may be extended to 71 months for high-risk children (e.g., sickle cell disease, HIV infection or other immunocompromising conditions, cochlear implant, or cerebrospinal fluid leaks).
• High-risk children aged 6 years and older: This permissive recommendation for an off-label use states: "[v]accination with a single dose of PCV13 may be appropriate for children 6 through 18 years of age who are at increased risk for pneumococcal disease".  Healthy older children should not receive the vaccine.
• Additional vaccine for children with underlying medical conditions: Children aged 2 years and older who are at increased risk for invasive pneumococcal disease should receive a 23-valent pneumococcal polysaccharide vaccine after vaccination with PCV13.

Post-marketing studies to include continued monitoring of the vaccine's safety as well as its efficacy in preventing invasive pneumococcal disease and otitis media will be conducted by the manufacturer.

On June 20, 2012, the Advisory Committee on Immunization Practices (ACIP) recommended routine use of 13-valent pneumococcal conjugate vaccine (PCV13; Prevnar 13) for adults aged ≥ 19 years with immunocompromising conditions, functional or anatomic asplenia, cerebrospinal fluid (CSF) leaks, or cochlear implants. ACIP reported as a Category A recommendation that PCV13 should be administered to eligible adults in addition to the 23-valent pneumococcal polysaccharide vaccine (PPSV23), the vaccine currently recommended for these groups of adults. Adults with specified immunocompromising conditions who are eligible for pneumococcal vaccine should be vaccinated with PCV13 during their next pneumococcal vaccination opportunity.

In pneumococcal vaccine-naive persons, ACIP recommends that adults aged ≥ 19 years with immunocompromising conditions, functional or anatomic asplenia, CSF leaks, or cochlear implants, and who have not previously received PCV13 or PPSV23, should receive a dose of PCV13 first, followed by a dose of PPSV23 at least 8 weeks later. They further recommended that subsequent doses of PPSV23 should follow current PPSV23 recommendations for adults at high risk, in which a second PPSV23 dose is recommended 5 years after the first PPSV23 dose for persons aged 19–64 years with functional or anatomic asplenia and for persons with immunocompromising conditions. The ACIP recommendations further state that “additionally, those who received PPSV23 before age 65 years for any indication should receive another dose of the vaccine at age 65 years, or later if at least 5 years have elapsed since their previous PPSV23 dose.” (Benett et al, 2012)

The ACIP recommendations specify that “adults aged ≥ 19 years with immunocompromising conditions, functional or anatomic asplenia, CSF leaks, or cochlear implants, who previously have received ≥ 1 doses of PPSV23 should be given a PCV13 dose ≥ 1 year after the last PPSV23 dose was received. For those who require additional doses of PPSV23, the first such dose should be given no sooner than 8 weeks after PCV13 and at least 5 years after the most recent dose of PPSV23.” (Bennett et al, 2012).

In August, 2014 the ACIP voted to recommend that patients 65 years of age and older receive Prevnar 13 vaccine to protect against pneumococcal bacteria that can cause pneumonia and other infections.  The recommendations state that adults 65 years of age or older who have not previously received either Prevnar 13 or Pneumovax, or whose previous vaccination history is unknown, should first receive a dose of Prevnar 13 followed by a dose of Pneumovax.  Adults in that age range who have not previously received Prevnar 13, but who have received Pneumovax, are noted in the recommendations as requiring a dose of Prevnar 13 (Reuters, 2014). The ACIP recommends the interval between PCV 13 and PPSV23 be 6-12 months.  The ACIP further recommended an interval of at least 1 year when PCV 13 is given post-PPSV23. The updated recommendations were based on recent data provided to the ACIP by the PCV-13 workgroup and by an effort to provide the benefits of PCV-13 as soon as possible to adults as evidence suggests that as indirect protection increases the effects of PCV 13 may lessen. Approximately 10 % vaccine update would prevent 5,000 pneumonia cases per year. The panel recommended a re-evaluation of Prevnar 13 in 2018 as, due to herd immunity, fewer individuals are expected to be prone to infections following the wider vaccination protocol (AHIP, 2014). In 2016, the ACIP determined that PCV 13 should be followed by PPSV23 by at least 1 year in all adults 65 years and older.

Burgess and Southern (2014) stated that invasive pneumococcal disease is associated with significant mortality and many countries have introduced routine pneumococcal vaccination into their childhood immunization programs.  While pneumococcal disease in cystic fibrosis (CF) is uncommon, pneumococcal immunization may offer some protection against pulmonary exacerbations caused by this pathogen.  In the USA and UK pneumococcal vaccination is currently recommended for all children and adults with CF.  In a Cochrane review, these investigators evaluated the effectiveness of pneumococcal vaccines in reducing morbidity in people with CF.  They searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Cystic Fibrosis Trials Register, which comprises references identified from comprehensive electronic database searches and hand-searches of relevant journals and abstract books of conference proceedings.  In addition, the pharmaceutical manufacturers of the polysaccharide and conjugate pneumococcal vaccines were approached.  Date of the most recent search was May 15, 2014.  Randomized and quasi-randomized controlled trials comparing pneumococcal vaccination (with either a polysaccharide or conjugate pneumococcal vaccine) with non-vaccination or placebo in children or adults with CF were eligible for inclusion.  No relevant trials were identified.  The authors concluded that as no trials were identified they could not draw conclusions on the effectiveness of routine pneumococcal immunization in people with CF in reducing their morbidity or mortality.  As many countries now include pneumococcal immunization in their routine childhood vaccination schedule it is unlikely that future randomized controlled trials will be initiated.  Rigorously conducted epidemiological studies may offer the opportunity to evaluate the effectiveness of pneumococcal vaccination in reducing morbidity and mortality in people with CF.

Hua et al (2014) evaluated the current literature on the impact of rheumatoid arthritis (RA) treatments on the humoral response to pneumococcal and influenza vaccines.  These investigators systematically searched the literature for studies evaluating the immune response to vaccines in RA patients receiving methotrexate (MTX) and/or biologic agents.  The effectiveness of vaccination, assessed by the response rate based on increased antibody titers before and 3 to 6 weeks after vaccination, was extracted by one investigator and verified by another.  A total of 12 studies were included.  Rheumatoid arthritis patients mainly received MTX, anti-tumor necrosis factor alpha (anti-TNFα), or rituximab (RTX).  Influenza vaccination response was reduced for RTX (43 patients; pooled odds ratio [OR] 0.44 [95 % CI: 0.17 to 1.12] for H1N1, OR 0.11 [95 % CI: 0.04 to 0.31] for H3N2, and OR 0.29 [95 % CI: 0.10 to 0.81] for B) but not for anti-TNFα (308 patients; OR 0.93 [95 % CI: 0.36 to 2.37] for H1N1, OR 0.79 [95 % CI: 0.34 to 1.83] for H3N2, and OR 0.79 [95 % CI: 0.37-1.70] for B).  For MTX, results differed depending on the method of analysis (222 patients; OR 0.35 [95 % CI: 0.18 to 0.66] for at least 2 strains, ORs were close to 1.0 in the single strain analysis).  Pneumococcal vaccination response was reduced for 139 patients receiving MTX compared with controls (OR 0.33 [95 % CI: 0.20 to 0.54] for serotype 6B and OR 0.58 [95 % CI: 0.36 to 0.94] for 23F) but not for anti-TNFα (258 patients; OR 0.96 [95 % CI: 0.57 to 1.59] for 6B and OR 1.20 [95 % CI: 0.57 to 2.54] for 23F).  For RTX, the response was reduced (88 patients; OR 0.25 [95 % CI: 0.11 to 0.58] for 6B and OR 0.21 [95 % CI: 0.04 to 1.05] for 23F).  The authors concluded that MTX decreased humoral response to pneumococcal vaccination and may impair response to influenza vaccination.  The immune response to both vaccines was reduced with RTX; but not with anti-TNFα therapy in RA patients.

Fortanier and colleagues (2014) stated that acute otitis media (AOM) is a very common respiratory infection in early infancy and childhood.  The marginal benefits of antibiotics for AOM in low-risk populations in general, the increasing problem of bacterial resistance to antibiotics and the huge estimated direct and indirect annual costs associated with otitis media (OM) have prompted a search for effective vaccines to prevent AOM.  These researchers examined the effect of pneumococcal conjugate vaccines (PCVs) in preventing AOM in children up to 12 years of age.  They searched CENTRAL (2013, Issue 11), MEDLINE (1995 to Week 3, November 2013), EMBASE (1995 to December 2013), CINAHL (2007 to December 2013), LILACS (2007 to December 2013) and Web of Science (2007 to December 2013).  Randomized controlled trials (RCTs) of PCVs to prevent AOM in children aged 12 years or younger, with a follow-up of at least 6 months after vaccination were selected for analysis.  Two review authors independently assessed trial quality and extracted data.  They included 11 publications of 9 RCTs (n = 48,426 children, range of 74 to 37,868 per study) of 7- to 11-valent PCV (with different carrier proteins).  Five trials (n = 47,108) included infants, while 4 trials (n = 1,318) included children aged 1 to 7 years that were either healthy (1 study, n = 264) or had a previous history of upper respiratory tract infection (URTI), including AOM.  These researchers judged the methodological quality of the included studies to be moderate to high.  There was considerable clinical diversity between studies in terms of study population, type of conjugate vaccine and outcome measures.  The authors therefore refrained from pooling the results.  In 3 studies, the 7-valent PCV with CRM197 as carrier protein (CRM197-PCV7) administered during early infancy was associated with a relative risk reduction (RRR) of all-cause AOM ranging from -5 % in high-risk children (95 % CI: -25 % to 12 %) to 7 % in low-risk children (95 % CI: 4 % to 9 %).  Another 7-valent PCV with the outer membrane protein complex of Neisseria meningitidis (N. meningitidis) serogroup B as carrier protein, administered in infancy, did not reduce overall AOM episodes, while a precursor 11-valent PCV with Haemophilus influenzae (H. influenzae) protein D as carrier protein was associated with a RRR of all-cause AOM episodes of 34 % (95 % CI: 21 % to 44 %).  A 9-valent PCV (with CRM197 carrier protein) administered in healthy toddlers was associated with a RRR of (parent-reported) OM episodes of 17 % (95 % CI: -2 % to 33 %).  CRM197-PCV7 followed by 23-valent pneumococcal polysaccharide vaccination administered after infancy in older children with a history of AOM showed no beneficial effect on first occurrence and later AOM episodes.  In a study in older children with a previously diagnosed respiratory tract infection, performed during the influenza season, a trivalent influenza vaccine combined with placebo (TIV/placebo) led to fewer all-cause AOM episodes than vaccination with TIV and PCV7 (TIV/PCV7) when compared to hepatitis B vaccination and placebo (HBV/placebo) (RRR 71 %, 95 % CI: 30 % to 88 % versus RRR 57 %, 95 % CI: 6 % to 80 %, respectively) indicating that CRM197-PCV7 after infancy may even have negative effects on AOM.  The authors concluded that based on current evidence of the effects of PCVs for preventing AOM, the licensed 7-valent CRM197-PCV7 has modest beneficial effects in healthy infants with a low baseline risk of AOM.  Administering PCV7 in high-risk infants, after early infancy and in older children with a history of AOM, appears to have no benefit in preventing further episodes.  Currently, several RCTs with different (newly licensed, multivalent) PCVs administered during early infancy are ongoing to establish their effects on AOM.  Results of these studies may provide a better understanding of the role of the newly licensed, multivalent PCVs in preventing AOM.  Also the impact on AOM of the carrier protein D, as used in certain pneumococcal vaccines, needs to be further established.

The FDA-approved indication for Prevnar 13 include the following (Pfizer, 2019):

• In children 6 weeks through 5 years of age (prior to the 6th birthday)
  
  
  • active immunization for the prevention of invasive disease caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F.
  • active immunization for the prevention of otitis media caused by S. pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F. No otitis media efficacy data are available for serotypes 1, 3, 5, 6A, 7F, and 19A.
    
    
• In children 6 years through 17 years of age (prior to the 18th birthday)
  
  
  • active immunization for the prevention of invasive disease caused by S. pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F. 
    
    
• In adults 18 years of age and older
  
  
  • active immunization for the prevention of pneumonia and invasive disease caused by S. pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F.
    
    
• Limitations: Prevnar 13 does not protect against disease caused by S. pneumoniae serotypes that are not in the vaccine. 

For children 6 weeks through 5 years, the four-dose immunization series consists of a 0.5 mL intramuscular injection administered at 2, 4, 6, and 12-15 months of age. For children 6 through 17 years of age, a single dose. For adults 18 years and older, a single dose (Pfizer, 2019).

The ACIP no longer recommends routine vaccination with PCV13 for all seniors (Freedman et al., 2020). Instead, vaccination should be based on shared decision-making. All seniors should still receive a dose of PPSV23.

The CDC reports that "incidence of PCV13-type disease has been reduced to historically low levels among adults aged ≥ 65 years through indirect effects from pediatric PCV13 use. Implementation of a PCV13 recommendation for all adults aged ≥ 65 years in 2014 has had minimal impact on PCV13-type disease at the population level in this age group. However, PCV13 is a safe and effective vaccine that can reduce the risk for PCV13-type IPD and noninvasive pneumonia among persons aged ≥ 65 years. Balancing this evidence and considering acceptability and feasibility concerns, in June 2019 ACIP voted to no longer routinely recommend PCV13 for all adults aged ≥ 65 years and instead, to recommend PCV13 based on shared clinical decision-making for adults aged ≥ 65 years who do not have an immunocompromising condition, CSF leak, or cochlear implant" (Matanock et al., 2019).  

The CDC recommends PCV13 for all children younger than 2 years of age, people 2 years or older with certain medical conditions, and adults 65 years or older who wish to discuss and decide with their clinician to get PCV13 and who do not have an immunocompromising condition, CSF leak, or cochlear implant (CDC, 2019).

The ACIP recommendations for those with certain medical conditions include the following (CDC, 2019):

• Children 2 through 5 years of age with:
  
  
  • Chronic heart disease
  • Chronic lung disease, including asthma if treated with high-dose oral corticosteroid therapy
  • Diabetes mellitus
    
    
• Persons 2 through 64 years of age with:
  
  
  • Anatomic or functional asplenia
  • Cerebrospinal fluid leaks
  • Chronic renal failure or nephrotic syndrome
  • Cochlear implant(s) 
  • Congenital or acquired immunodeficiency (including HIV infection)
  • Generalized and metastatic malignancies
  • Hodgkin disease
  • Iatrogenic immunosuppression, including radiation therapy
  • Leukemia or lymphoma
  • Multiple myeloma
  • Sickle cell disease or other hemoglobinopathies
  • Solid organ transplant

Elective Splenectomy

An UpToDate review on “Prevention of sepsis in the asplenic patient” (Pasternack, 2016) states the following:

If a patient has anatomic or functional asplenia, we recommend immunization with pneumococcal, meningococcal, and Haemophilus influenzae type b vaccine.

If a patient will be undergoing elective splenectomy, we recommend that the pneumococcal, meningococcal, and Haemophilus influenzae vaccines be administered at least 14 days prior to surgery.  If it is not possible to administer these vaccines prior to splenectomy, they can be given after the 14th post-operative day.

Intra-Nasal Pneumococcal Vaccine

Li and colleagues (2018) stated that Streptococcus pneumoniae is a major respiratory tract pathogen causing high levels of mortality and morbidity in infants and the elderly.  In spite of the multitude of capsular polysaccharide vaccines used to guard against pneumococcal disease, fatal pneumococcal disease remains epidemic.  Immunization with pneumococcal surface protein A (PspA), a highly immunogenic surface protein present in all strains of S. pneumoniae, can elicit protection against deadly pneumococcal infection.  These investigators had previously evaluated PspA in systemic vaccination.  However, the mucosal immune system, as a 1st-line of defense against respiratory infection, plays the most important role against the invasion of S. pneumoniae.  In this study, these researchers employed bacterium-like particles (BLPs) as an adjuvant for a PspA mucosal vaccine.  The BLPs served as a carrier for PspA proteins bound to their surface.  Mice were immunized intra-nasally with the PspA-BLP pneumococcal vaccine consisting of PspA3 from pneumococcal family 2.  Not only did the immunized mice show a high level of serum IgG antibodies but also a high level of SIgA antibodies in the respiratory tract.  After immunization with the PspA3-BLP vaccine, the mice were broadly protected against fatal intra-nasal challenge with homologous and heterogeneous pneumococcal strains of different PspA families regardless of serotype, and the colony count was notably decreased in the lungs.  The authors concluded that the PspA3-BLP pneumococcal vaccine has the potential to serve as a novel mucosal vaccine to enhance both systemic and mucosal immune responses to this disease.

Yu and associates (2018) vaccinated mice via the subcutaneous (s.c.) route with a systemic vaccine that is a mixture of fusion protein PsaA-PspA23 and a single protein, PspA4, with aluminum hydroxide as an adjuvant.  As a comparison, mice were immunized intra-nasally with a mucosal vaccine that is a mixture of PspA2-PA-BLP (where PA is protein anchor and BLP is bacterium-like particle) and PspA4-PA-BLP, via the intra-nasal (i.n.) route.  The 2 immunization processes were followed by challenge with Streptococcus pneumoniae bacteria from 2 different PspA families.  Specific IgG titers in the serum and specific IgA titers in the mucosa were determined following immunizations.  Bacterial loads and survival rates after challenge were compared.  Both the systemic vaccine and the mucosal vaccine induced a significant increase of IgG against PspAs.  Only the mucosal vaccine also induced specific IgA in the mucosa.  The 2 vaccines provided protection, but each vaccine showed an advantage.  The authors concluded that the systemic vaccine induced higher levels of serum antibodies, whereas the mucosal vaccine limited the bacterial load in the lung and blood.  These researchers stated that co-immunizations with the 2 types of vaccines may be implemented in the future.

Lu and co-workers (2019) applied BLPs as an adjuvant for the development of a PspA mucosal vaccine, in which the PspA protein was displayed on the surface of BLPs.  Intra-nasal immunization with the PspA-BLP pneumococcal vaccine, comprised of PspA2 from pneumococcal family 1 and PspA4 from pneumococcal family 2, not only induced a high level of serum IgG antibodies but also a high level of mucosal SIgA antibodies.  Analysis of binding of serum antibodies to intact bacteria showed a broad coverage of binding to pneumococcal strains expressing PspA from clade 1 to 5.  Immunization with the PspA-BLP vaccine conferred protection against fatal intranasal challenge with both PspA family 1 and family 2 pneumococcal strains regardless of serotype.  The authors concluded that the PspA-BLP pneumococcal vaccine was demonstrated to be a promising strategy for mucosal immunization to enhance both systemic and mucosal immune responses.

Pneumococcal Vaccination in Adult Solid Organ Transplant Recipients

Dendle and colleagues (2018) summarized the current literature relating to pneumococcal vaccination in adult solid organ transplant (SOT) recipients, who are at risk of invasive pneumococcal disease (IPD) with its attendant high morbidity and mortality.  The effect of the pneumococcal polysaccharide vaccine has been examined in several small cohort studies in SOT recipients, most of which were kidney transplant recipients.  The outcomes for these studies have been laboratory sero-responses or functional antibody titers.  Overall, in most of these studies the transplant recipients were capable of generating measurable serological responses to pneumococcal vaccination but these responses were less than those of healthy controls.  A mathematical model estimated the effectiveness of polysaccharide vaccination in SOT recipients to be 1/3 less than those of patients with HIV.  The evidence for the efficacy of the pneumococcal conjugate vaccine in SOT is based on a small number of RCTs in liver and kidney transplant recipients.  These trials demonstrated that SOT recipients mounted a serological response following vaccination; however there was no benefit to the use of prime boosting (conjugate vaccine followed by polysaccharide vaccine).  Currently there are no randomized studies investigating the clinical protection rate against IPD after pneumococcal vaccination by either vaccine type or linked to vaccine titers or other responses against pneumococcus.  Concerns that vaccination may increase the risk of adverse allo-responses such as rejection and generation of donor specific antibodies are not supported by studies examining this aspect of vaccine safety.  The authors concluded that pneumococcal vaccination is a potentially important strategy to reduce IPD in SOT recipients and is associated with excellent safety.  Current international recommendations are based on expert opinion from conflicting data, hence there is a clear need for further high-quality studies in this high-risk population examining optimal vaccination regimens.  Such studies should focus on strategies to optimize functional immune responses.

Prevention of Acute Exacerbations of COPD in Persons with Moderate, Severe, or Very Severe COPD

The American College of Chest Physicians and Canadian Thoracic Society guideline on “Prevention of acute exacerbations of COPD” (Criner et al, 2015) states that in patients with COPD, the panel suggests administering the 23-valent pneumococcal vaccine as part of overall medical management; but did not find sufficient evidence that pneumococcal vaccination prevents acute exacerbations of COPD (Grade 2C).

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
CPT codes covered if selection criteria are met:
90670	Pneumococcal conjugate vaccine, 13 valent, for intramuscular use
90732	Pneumococcal polysaccharide vaccine, 23-valent, adult or immunosuppressed patient dosage, when administered to individuals 2 years or older, for subcutaneous or intramuscular use
Other CPT codes related to the CPB:
90460	Immunization administration through 18 years of age via any route of administration, with counseling by physician or other qualified health care professional; first or only component of each vaccine or toxoid administered
+90461	each additional vaccine or toxoid component administered (List separately in addition to code for primary procedure)
90471	Immunization administration (includes percutaneous, intradermal, subcutaneous, or intramuscular injections); 1 vaccine (single or combination vaccine/toxoid)
+90472	each additional vaccine (single or combination vaccine/toxoid) (List separately in addition to code for primary procedure)
HCPCS codes covered if selection criteria are met:
G0009	Administration of pneumococcal vaccine
S0195	Pneumococcal conjugate vaccine, polyvalent, intramuscular, for children from 5 years to 9 years of age who have not previously received the vaccine
ICD-10 codes covered if selection criteria are met:
Z23	Encounter for immunization [pneumococcus]

The above policy is based on the following references: