Pneumococcal Vaccines Form

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 %).

Advisory Committee on Immunization Practices (ACIP) Recommendations

There are 2 types of pneumococcal vaccines available in the United States: Pneumococcal conjugate vaccines (PCV13, PCV15, and PCV20) and pneumococcal polysaccharide vaccine (PPSV23).

On October 20, 2021, the ACIP recommended 15-valent PCV (PCV15) or 20-valent PCV (PCV20) for PCV–naïve adults who are either aged 65 years or older or aged 19 through 64 years with certain underlying conditions. When PCV15 is used, it should be followed by a dose of PPSV23, typically 1 year or more later.

On June 22, 2022, ACIP updated the recommendations for use of the PCV15 among U.S. children as an option for pneumococcal conjugate vaccination for persons less than 19 years of age, according to currently recommended PCV13 dosing and schedules. Risk-based recommendations on use of PPSV23 were not changed. ACIP recommends use of PCV (either PCV13 or PCV15) for all children aged 2 months through 59 months. In addition, risk-based PCV use is recommended for children aged 60 through 71 months with risk conditions, and persons aged 6 years through 18 years with an immunocompromising condition, cerebrospinal fluid leak, or cochlear implant. For all recommendations, PCV13 and PCV15 can be used interchangeably. Interruption of the vaccination schedule does not require reinstitution of the entire series or the addition of extra doses (Kobayashi et al, 2022b).

The following ACIP recommendations for pneumococcal vaccination were published on the CDC's websites:

Children Younger than 2 Years Old

CDC recommends PCV13 or PCV15 for all infants as a series of 4 doses: Give 1 dose at 2 months, 4 months, 6 months, and 12 through 15 months.

Children 2 through 4 Years Old without Certain Medical Conditions

CDC recommends PCV13 or PCV15 vaccination for children 2 through 4 years old who are unvaccinated or received an incomplete pneumococcal conjugate vaccine (either PCV13 or PCV15) series. PCV13 and PCV15 can be used interchangeably. Give 1 dose of PCV13 or PCV15.

Children 2 through 5 Years Old with Certain Medical Conditions

CDC recommends 2 doses of either PCV13 or PCV15 if they are unvaccinated or received an incomplete PCV13 series with less than 3 doses before 24 months of age. Give the second dose at least 8 weeks after the first, or 1 dose of PCV13 or PCV15 if they received 3 doses of pneumococcal conjugate vaccine before 12 months of age but have not received their fourth booster dose; and 1 dose of PPSV23 at least 8 weeks after the pneumococcal conjugate vaccine series is complete for the children with the following medical conditions:

Cerebrospinal fluid leak

Chronic heart disease, particularly cyanotic congenital heart disease and cardiac failure

Chronic lung disease, including asthma if treated with prolonged high-dose oral corticosteroid therapy

Cochlear implant

Diabetes mellitus

CDC recommends 2 doses of PCV13 or PCV15 if they are unvaccinated or received an incomplete pneumococcal conjugate vaccine series with less than 3 doses before 24 months of age. Give the second dose at least 8 weeks after the first, or 1 dose of PCV13 or PCV15 if they received 3 doses of a pneumococcal conjugate vaccine before12 months of age but have not received their fourth booster dose, and 2 doses of PPSV23 after the pneumococcal conjugate vaccine series is complete. Give the first dose at least 8 weeks after any prior pneumococcal conjugate vaccine dose, then give the second dose of PPSV23 at least 5 years after the first PPSV23 dose for children with any of these conditions:

Chronic renal failure or nephrotic syndrome

Congenital immunodeficiency

B- (humoral) or T-lymphocyte deficiency

Complement deficiency, particularly C1, C2, C3, or C4 deficiency

Phagocytic disorder, excluding chronic granulomatous disease

Congenital or acquired asplenia, or splenic dysfunction

Diseases associated with treatment of immunosuppressive drugs or radiation therapy

Hodgkin disease

Leukemia

Lymphoma

Malignant neoplasm

Solid organ transplant

HIV infection

Sickle cell disease or other hemoglobinopathies.

Children 6 through 18 Years Old with Certain Medical Conditions

CDC recommends 1 dose of a pneumococcal conjugate vaccine (either PCV13 or PCV15) if they have not received any doses of a pneumococcal conjugate vaccine. Administer PCV13 or PCV15 before giving any recommended doses of PPSV23, and 1 dose of PPSV23 (if not already given earlier in childhood) at least 8 weeks after PCV13 or PCV15 for children with any of these conditions:

Cerebrospinal fluid leak

Cochlear implant

CDC recommends 1 dose of a pneumococcal conjugate vaccine (either PCV13 or PCV15) if they have not received any doses of a pneumococcal conjugate vaccine. Administer PCV13 or PCV15 before giving any recommended doses of PPSV23. Ensure the child receives 2 doses of PPSV23. The first dose of PPSV23 should be given at least 8 weeks after any prior pneumococcal conjugate vaccine dose, then the second dose of PPSV23 should be given at least 5 years after the first dose of PPSV23 for children with any of these conditions:

Chronic renal failure or nephrotic syndrome

Congenital immunodeficiency

B- (humoral) or T-lymphocyte deficiency

Complement deficiency, particularly C1, C2, C3, or C4 deficiency

Phagocytic disorder, excluding chronic granulomatous disease

Congenital or acquired asplenia, or splenic dysfunction

Diseases associated with treatment of immunosuppressive drugs or radiation therapy

Hodgkin disease

Leukemia

Lymphoma

Malignant neoplasm

Solid organ transplant

HIV infection

Sickle cell disease or other hemoglobinopathies

CDC recommends 1 dose of PPSV23 (if not already given earlier in childhood) for children with any of these conditions:

Chronic heart disease, particularly cyanotic congenital heart disease and cardiac failure

Chronic lung disease, including asthma if treated with prolonged high-dose oral corticosteroid therapy

Diabetes mellitus

Adults 19 through 64 Years Old Who Have Certain Chronic Medical Conditions or Other Risk Factors

For adults with any of the following conditions or risk factors:

Alcoholism

Cerebrospinal fluid leak

Chronic heart disease, including congestive heart failure and cardiomyopathies

Chronic liver disease

Chronic lung disease, including chronic obstructive pulmonary disease, emphysema, and asthma

Chronic renal failure

Cigarette smoking

Cochlear implant

Congenital or acquired asplenia

Congenital or acquired immunodeficiency

B- (humoral) or T-lymphocyte deficiency

Complement deficiency, particularly C1, C2, C3, or C4 deficiency

Phagocytic disorder, excluding chronic granulomatous disease

Diabetes mellitus

Generalized malignancy

HIV infection

Hodgkin disease

Iatrogenic immunosuppression, including long-term systemic corticosteroids and radiation therapy

Leukemia

Lymphoma

Multiple myeloma

Nephrotic syndrome

Sickle cell disease or other hemoglobinopathies

Solid organ transplant

For those who have not previously received any pneumococcal vaccine, CDC recommends:

1 dose of PCV15 or PCV20

If PCV15 is used, this should be followed by a dose of PPSV23 at least one year later. The minimum interval is 8 weeks and can be considered in adults with an immunocompromising condition, cochlear implant, or cerebrospinal fluid leak.

If PCV20 is used, a dose of PPSV23 is NOT indicated.

For those who have only received PPSV23, CDC recommends:

1 dose of PCV15 or PCV20.

The PCV15 or PCV20 dose should be administered at least one year after the most recent PPSV23 vaccination.

Regardless of if PCV15 or PCV20 is given, an additional dose of PPSV23 is not recommended since they already received it.

For those who have received PCV13 with or without PPSV23, CDC recommends PPSV23 as previously recommended. The incremental public health benefits of providing PCV15 or PCV20 to adults who have received PCV13 only or both PCV13 and PPSV23 have not been evaluated.

Adults 65 Years or Older

CDC recommends pneumococcal vaccination for all adults 65 years or older.

For adults 65 years or older who have not previously received any pneumococcal vaccine, CDC recommends:

1 dose of PCV15 or PCV20

If PCV15 is used, this should be followed by a dose of PPSV23 at least one year later. The minimum interval is 8 weeks and can be considered in adults with an immunocompromising condition, cochlear implant, or cerebrospinal fluid leak.

If PCV20 is used, a dose of PPSV23 is NOT indicated.

For adults 65 years or older who have only received a PPSV23, CDC recommends:

1 dose of PCV15 or PCV20

The PCV15 or PCV20 dose should be administered at least one year after the most recent PPSV23 vaccination.

Regardless of if PCV15 or PCV20 is given, an additional dose of PPSV23 is not recommended since they already received it.

For adults 65 years or older who have only received PCV13, CDC recommends:

Give PPSV23 as previously recommended. The incremental public health benefits of providing PCV15 or PCV20 to adults who have received PCV13 only or both PCV13 and PPSV23 have not been evaluated.

For adults who have received PCV13 but have not completed their recommended pneumococcal vaccine series with PPSV23, one dose of PCV20 may be used if PPSV23 is not available. If PCV20 is used, their pneumococcal vaccinations are complete.

On June 22, 2023, the Pneumococcal Vaccines Work Group for ACIP met to review the evidence on recommendations for use of PCV20 in children. They voted to add the 20-valent vaccine as an option for pediatrics and expanded its definition of high-risk children to include those with moderate persistent and severe persistent asthma. These recommendations were adopted by the CDC Director on June 27, 2023 and are now official. They will be published in MMWR in the coming months (CDC, 2023):

Use of either pneumococcal conjugate vaccines (PCV) PCV15 or PCV20 is recommended for all children aged 2–23 months according to currently recommended PCV dosing and schedules.

For children with an incomplete PCV vaccination status, use of either PCV15 or PCV20 according to currently recommended PCV dosing and schedules is recommended for:

Healthy children aged 24–59 months

Children with specified health conditions

Footnote3 ***

aged 24 through 71 months

For children aged 2–18 years with any risk condition who have received all recommended doses of PCV before age 6 years

Using ≥1 dose(s) of PCV20: No additional doses of any pneumococcal vaccine are indicated. This recommendation may be updated as additional data become available.

Using PCV13 or PCV15 (no PCV20): A dose of PCV20 or PPSV23 using previously recommended dosing and schedules is recommended.

For children aged 6–18 years with any risk condition who have not received any dose of PCV13, PCV15, or PCV20, a single dose of PCV15 or PCV20 is recommended. When PCV15 is used, it should be followed by a dose of PPSV23 at least 8 weeks later if not previously given.

Footnote3

*** Risk conditions include: cerebrospinal fluid leak; chronic heart disease; chronic kidney disease (excluding maintenance dialysis and nephrotic syndrome, which are included in immunocompromising conditions); chronic liver disease; chronic lung disease (including moderate persistent or severe persistent asthma); cochlear implant; diabetes mellitus; immunocompromising conditions (on maintenance dialysis or with nephrotic syndrome; congenital or acquired asplenia or splenic dysfunction; congenital or acquired immunodeficiencies; diseases and conditions treated with immunosuppressive drugs or radiation therapy, including malignant neoplasms, leukemias, lymphomas, Hodgkin disease, and solid organ transplant; HIV infection; and sickle cell disease and other hemoglobinopathies) (CDC, 2023).

Pneumococcal Polysaccharide Vaccine (PPSV23)

Pneumococcal polyvalent vaccine is available as Pneumovax 23 (Merck & Co., Inc) and is supplied as a 0.5 mL single-dose vial and a single-dose prefilled syringe for intramuscular or subcutaneous injection. Pneumovax 23 is FDA approved for use in persons 50 years of age or older and persons aged 2 years and older who are at increased risk for pneumococcal disease. Pneumovax 23 is not approved for use in children younger than 2 years of age because children in this age group do not develop an effective immune response to capsular types contained in the polysaccharide vaccine. Response to vaccination may be diminished in immunocompromised individuals.

Pneumovax 23 is a vaccine 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, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F, and 33F).

Pneumococcal polysaccharide vaccine (Pneumovax 23) 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.

Pneumococcal vaccine may be given with other vaccines. No data indicate that administration of pneumococcal vaccine with DTP, poliovirus, or influenza increases the severity of reactions or diminishes the responses. However, 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. Thus, it is recommended that administration of the two vaccines be separated by at least 4 weeks (Merck, 2021b).

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.

For subjects aged 65 years or older in a clinical study systemic adverse reactions, determined by the investigator to be vaccine-related, were higher following revaccination (33.1%) than following initial vaccination (21.7%). Routine revaccination of immunocompetent persons previously vaccinated with a 23-valent vaccine, is not recommended.

The most common adverse reactions, reported in more than 10% of subjects vaccinated with Pneumovax 23 for the first time in a clinical trial, were: injection-site pain/soreness/tenderness (60.0%), injection-site swelling/induration (20.3%), headache (17.6%), injection-site erythema (16.4%), asthenia and fatigue (13.2%), and myalgia (11.9%) (Merck, 2021b).

Heptavalent Pneumococcal Conjugate Vaccine (PCV7)

A 7-valent pneumococcal conjugate vaccine (Prevnar™, Prevenar

™

) was introduced by Wyeth Lederle for use in children. The FDA had 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 had 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 had recommended 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.

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.

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

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

U.S. Food and Drug Administration (FDA)-Approved Indications

In children 6 weeks through 5 years of age (prior to the 6th birthday), Prevnar 13 is indicated for:

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), Prevnar 13 is indicated for:

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, Prevnar 13 is indicated for:

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 of Prevnar 13 Use and Effectiveness

Prevnar 13 does not protect against disease caused by S. pneumoniae serotypes that are not in the vaccine.

Pneumococcal 13-valent conjugate vaccine is available as Prevnar 13 (Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer Inc) and is supplied in a single-dose prefilled syringe as 0.5 mL suspension for intramuscular injection.

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 sixth 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.

Labeled warnings and precautions include apnea following intramuscular vaccination which has been observed in some infants born prematurely. Decisions about when to administer an intramuscular vaccine, including Prevnar 13, to infants born prematurely should be based on consideration of the individual infant's medical status, and the potential benefits and possible risks of vaccination.

Adverse reactions, per the label, include the following:

In infants and toddlers vaccinated at 2, 4, 6, and 12–15 months of age in US clinical trials, the most commonly reported solicited adverse reactions (greater than 5%) were irritability (greater than 70%), injection site tenderness (greater than 50%), decreased appetite (greater than 40%), decreased sleep (greater than 40%), increased sleep (greater than 40%), fever (greater than 20%), injection site redness (greater than 20%), and injection site swelling (greater than 20%).

In children aged 5 through 17 years, the most commonly reported solicited adverse reactions (greater than 5%) were injection site tenderness (greater than 80%), injection site redness (greater than 30%), injection site swelling (greater than 30%), irritability (greater than 20%), decreased appetite (greater than 20%), increased sleep (greater than 20%), fever (greater than 5%), and decreased sleep (greater than 5%).

In adults aged 18 years and older, the most commonly reported solicited adverse reactions (greater than 5%) were pain at the injection site (greater than 50%), fatigue (greater than 30%), headache (greater than 20%), muscle pain (greater than 20%), joint pain (greater than 10%), decreased appetite (greater than 10%), injection site redness (greater than 10%), injection site swelling (greater than 10%), limitation of arm movement (greater than 10%), vomiting (greater than 5%), fever (greater than 5%), chills (greater than 5%), and rash (greater than 5%).

Pneumococcal 15-valent Conjugate Vaccine (PCV15, Vaxneuvance)

Pneumococcal 15-valent conjugate vaccine is available as Vaxneuvance (Merck & Co., Inc) which is supplied as a single-dose prefilled syringe of 0.5 mL suspension for intramuscular injection. In July 2021, the FDA approved Vaxneuvance for 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, 22F, 23F and 33F in individuals 6 weeks of age and older. Protection against invasive disease is conferred mainly by opsonophagocytic killing of S. pneumoniae. Vaxneuvance induces opsonophagocytic activity against the serotypes contained in the vaccine.

FDA approval was based on data from seven randomized, double-blind clinical studies assessing safety, tolerability, and immunogenicity in adults. Clinical data showed that immune responses elicited by Vaxneuvance were non-inferior to the currently available 13-valent pneumococcal conjugate vaccine (PCV13) for the 13 shared serotypes, as assessed by opsonophagocytic activity (OPA) Geometric Mean Titers (GMTs). Additionally, immune responses for Vaxneuvance were superior to PCV13 for shared serotype 3 and for the two serotypes unique to Vaxneuvance, 22F and 33F. In the pivotal Phase 3 PNEU-AGE (V114-019) study, superiority for Vaxneuvance relative to PCV13 was based on statistically significantly greater OPA GMT ratios for serotypes 22F [GMT Ratio 32.52 (95% Confidence Interval (CI) 25.87, 40.88)] and 33F [GMT Ratio 7.19 (95% CI 6.13, 8.43)], as well as for the key secondary objective assessing serotype 3 [GMT Ratio 1.62 (95% CI 1.40, 1.87)]. Randomized controlled trials assessing the clinical efficacy of Vaxneuvance compared to PCV13 have not been conduct ed (Merck, 2021a). In 2022, the label for Vaxneuvance was expanded to include children and adolescence. FDA approval was based on double-blind, active comparator-controlled studies that randomized infants, children and adolescents to receive Vaxneuvance or Prevnar 13 in a 4-dose series or receiving catch-up vaccination. Vaxneuvance was found to be noninferior to Prevnar 13, and for the catch-up vaccination study, Vaxneuvance elicited immune responses, as assessed by serotype-specific IgG GMCs at 30 days following the last dose of vaccine, in children 7 months through 17 years of age that were numerically similar to Prevnar 13 for the shared serotypes and higher than Prevnar 13 for the unique serotypes 22F and 33F. Within each age cohort, serotype-specific IgG GMCs at 30 days following the last dose of vaccine were numerically similar between the vaccination groups for the 13 shared serotypes and higher in Vaxneuvance for the 2 unique serotypes (Merk, 2022).

Some individuals with altered immunocompetence, including those receiving immunosuppressive therapy, may have a reduced immune response to Vaxneuvance.

There are no adequate and well-controlled studies of Vaxneuvance in pregnant women. Available data on Vaxneuvance administered to pregnant women are insufficient to inform vaccine-associated risks in pregnancy. In addition, human data are not available to assess the impact on milk production, its presence in breast milk, or its effects on the breastfed child.

Warnings and precautions in the prescribing information state that apnea following intramuscular vaccination has been observed in some infants born prematurely. A decision about when to administer Vaxneuvance to infants born prematurely should be based on consideration of the individual infant’s medical status and the potential benefits and possible risks of vaccination.

Per the label, the most commonly reported solicited adverse reactions include the following:

In children vaccinated with a 4-dose series at 2, 4, 6 and 12 through 15 months of age, provided as a range across the series, were: irritability (57.3% to 63.4%), somnolence (24.2% to 47.5%), injection-site pain (25.9% to 40.3%), fever ≥38.0°C (13.3% to 20.4%), decreased appetite (14.1% to 19.0%), injection-site induration (13.2% to 15.4%), injection-site erythema (13.7% to 21.4%) and injection-site swelling (11.3% to 13.4%).

In children and adolescents 2 through 17 years of age vaccinated with a single dose were: injection-site pain (54.8%), myalgia (23.7%), injection-site swelling (20.9%), injection-site erythema (19.2%), fatigue (15.8%), headache (11.9%) and injection-siteinduration (6.8%). (

In individuals 18 through 49 years of age were: injection-site pain (75.8%), fatigue (34.3%), myalgia (28.8%), headache (26.5%), injection-site swelling (21.7%), injection-site erythema (15.1%) and arthralgia (12.7%).

In individuals 50 years of age and older were: injection-site pain (66.8%), myalgia (26.9%), fatigue (21.5%), headache (18.9%), injection-site swelling (15.4%), injection-site erythema (10.9%) and arthralgia (7.7%).

Pneumococcal 20-valent Conjugate Vaccine (PCV20, Prevnar 20)

Pneumococcal 20-valent conjugate vaccine is available as Prevnar 20 (Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer Inc) and is supplied in a single-dose pre-filled syringe of 0.5 mL suspension for intramuscular injection. Prevnar 20 was FDA approved in April 2023 for active immunization for the prevention of the following:

invasive pneumococcal disease (IPD) caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F, and 33F in individuals 6 weeks of age and older;

otitis media caused by S. pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F in individuals 6 weeks through 5 years of age;

pneumonia caused by S. pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F, and 33F in individuals 18 years of age and older.

Per the label, the indication for the prevention of pneumonia caused by S. pneumoniae serotypes 8, 10A, 11A, 12F, 15B, 22F, and 33F in individuals 18 years of age and older is approved under accelerated approval based on immune responses as measured by opsonophagocytic activity (OPA) assay. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Prevnar 20 includes capsular polysaccharide conjugates for the 13 serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F) already included in Prevnar 13 (pneumococcal 13-valent conjugate vaccine [diphtheria CRM

₁₉₇

protein]). The vaccine also contains capsular polysaccharide conjugates for seven additional serotypes (8, 10A, 11A, 12F, 15B, 22F and 33F) that cause invasive pneumococcal disease (IPD) and have been associated with high case-fatality rates, antibiotic resistance, and/or meningitis (Pfizer, 2021).

The FDA approved Prevnar 20 for the prevention of invasive disease and pneumonia in adults 18 years of age and older in June 2021. FDA approval was based on evidence from Pfizer’s clinical program in adults, including Phase 1 and 2 trials, and three Phase 3 trials (NCT03760146, NCT03828617, and NCT03835975) describing the safety and evaluating the immunogenicity of the vaccine. More than 6,000 adult subjects 18 years and older participated in the three Phase 3 trials, including adults 65 years of age and older, vaccine-naïve adults, and adults with prior pneumococcal vaccination (Pfizer, 2021).

FDA approval for use in children is based on results demonstrated in phase 2 and phase 3 clinical trials, including three core phase 3 pediatric studies that contributed to the data on the safety, tolerability, and immunogenicity of Prevnar 20. For more information on trial outcomes, see the section on Clinical Studies in

Prevnar 20 - Full Prescribing Information

(Pfizer, 2023, Wyeth Pharmaceuticals, 2023).

There are no adequate and well-controlled studies of Prevnar 20 in pregnant women. It is not known whether Prevnar 20 is excreted in human milk.

Prevnar 20 is administered to children as a 4-dose immunization series at 2, 4, 6, and 12 through 15 months of age. For adults 18 years of age and older, Prevnar 20 is administered as a single dose.

The effectiveness of Prevnar 20 for the prevention of pneumonia has not been established in individuals younger than 18 years of age. In addition, the safety and effectiveness of Prevnar 20 in individuals younger than 6 weeks of age have not been established (Wyeth Pharmaceuticals, 2023).

Per the label, Prevnar 20 is contraindicated for those who are allergic to any component of Prevnar 20 or to diphtheria toxoid. Warnings and precautions include apnea following intramuscular vaccination which has been observed in some infants born prematurely, and that decisions about when to administer Prevnar 20 to infants born prematurely should be based on consideration of the individual infant’s medical status, and the potential benefits and possible risks of vaccination.

Adverse reactions include the following:

In individuals 2, 4, 6, and 12 through 15 months of age vaccinated with a 4‑dose schedule, the most commonly reported solicited adverse reactions greater than 10% were irritability (greater than 60%), pain at the injection site (greater than 30%), drowsiness (greater than 30%), decreased appetite and injection site redness (greater than 20%), injection site swelling (greater than 10%), and fever (greater than 10%).

In individuals 15 months through 17 years of age vaccinated with a single dose, the most commonly reported solicited adverse reactions greater than 10% were irritability (greater than 60% in individuals less than 2 years of age), pain at the injection site (greater than 50%), drowsiness (greater than 40% in individuals less than 2 years of age), fatigue and muscle pain (greater than 20% in individuals 2 years of age and older), decreased appetite (greater than 20% in individuals less than 2 years of age), injection site swelling and injection site redness (greater than 10%) and headache (greater than 10% in individuals 5 years of age and older), and fever (greater than 10% in individuals less than 2 years of age).

In individuals 18 through 59 years of age, the most commonly reported solicited adverse reactions greater than 10% were pain at the injection site (greater than 70%), muscle pain (greater than 50%), fatigue (greater than 40%), headache (greater than 30%), and arthralgia and injection site swelling (greater than 10%).

In individuals 60 years of age and older, the most commonly reported solicited adverse reactions greater than 10% were pain at the injection site (greater than 50%), muscle pain and fatigue (greater than 30%), headache (greater than 20%), and arthralgia (greater than 10%).

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).

On October 20, 2021, the CDC's ACIP updated the pneumococcal vaccine recommendations for adults aged 65 years and older. See ACIP recommendations section.

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.

Immune Response to Vaccines in Rheumatoid Arthritis

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.

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 first-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).

Prevention of Acute Otitis Media

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.

Reducing Morbidity and Mortality in Persons with Cystic Fibrosis

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.

Scope of Policy

This Clinical Policy Bulletin addresses pneumococcal vaccines.

Medical Necessity

Aetna considers pneumococcal conjugate vaccines (PCV13, PCV15, and PCV20) and pneumococcal polysaccharide vaccine (PPSV23) medically necessary according to the recommendations of the Centers for Disease Control and Prevention’s (CDC) Advisory Committee on Immunization Practices (ACIP). The following pneumococcal vaccines are considered medically necessary (unless otherwise specified):

Summary of Recommendations

Adults:

ACIP recommends 15-valent PCV (PCV15) or 20-valent PCV (PCV20) for PCV–naïve adults who are either aged 65 years or older, or aged 19 to 64 years with certain underlying conditions

Footnote1 *

. When PCV15 is used, it should be followed by a dose of PPSV23, typically greater than or equal to 1 year later. Eligible adults may receive either PCV15 in series with PPSV23 or PCV20 alone (Kobayashi et al, 2022a).

Children:

ACIP recommends routine use of PCV15 or PCV20 in children ages 2-23 months according to currently recommended dosing and schedules. PCV15 or PCV20 is recommended according to the current dosing and schedule as catch-up vaccination for healthy children ages 24 to 59 months and for those 24 to 71 months with certain underlying medical conditions

Footnote2 **

that increase the risk of pneumococcal disease. For ages 2 to 18 years who are already up to date on all PCV doses before 6 years of age, no more doses are recommended if received at least one dose of PCV20. However, if received PCV13 or PCV15, the recommendation is for one dose of PCV20 or the PPSV23. Children ages 6-18 years with a risk condition

Footnote2 **

who have not received PCV13, PCV15, or PCV20, a single dose of PCV15 or PCV20 is recommended at least 8 weeks after the most recent dose. If PCV15 is used, a follow-up dose of PPSV23 is recommended at least 8 weeks later.

Infants, children, adolescence

Pneumococcal 13-valent conjugate vaccine (PCV13, e.g., Prevnar 13) for

either

of the following:

All infants / children 2 months through 59 months of age (less than 5 years of age);

Children / adolescence 5 through 18 years of age who have underlying health conditions

Footnote2 **

that increase risk for pneumococcal disease;

Pneumococcal 15-valent conjugate vaccine (PCV15, e.g., Vaxneuvance) or pneumococcal 20-valent conjugate vaccine (PCV20, e.g., Prevnar 20) for all children aged 2 through 23 months according to currently recommended PCV dosing and schedules;

Children with an incomplete PCV vaccination status, use of either PCV15 or PCV20 according to current PCV dosing and schedule as catch-up vaccination for:

Healthy children aged 24 through 59 months (2 years to less than 5 years of age);

or

Children aged 24 through 71 months (2 years to less than 6 years of age) who have underlying health conditions

Footnote2 **

that increase risk for pneumococcal disease;

Children aged 2 through 18 years with any risk condition who have received all recommended doses of PCV before age 6 years;

and

Received at least one dose of PCV20, additional doses of any pneumococcal vaccine are considered not medically necessary;

or

Received PCV13 or PCV15 and did not receive a PCV20 vaccine, a dose of PCV20 or 23-valent pneumococcal polysaccharide vaccine (PPSV23, e.g., Pneumovax 23) is considered considered medically necessary;

Children aged 6 through 18 years with any risk condition who have not received any dose of PCV13, PCV15, or PCV20, a single dose of PCV15 or PCV20 is considered medically necessary.

Note:

When PCV15 is used, a follow-up dose of PPSV23 is recommended by the ACIP to be administered at least 8 weeks later if not previously given;

Adults 19 through 64 years

PCV15 or PCV20 for adults 19 through 64 years of age who have underlying health conditions

Footnote *

that increase risk for pneumococcal disease;

PPSV23 for adults 19 through 64 years of age who have underlying health conditions

Footnote1 *

and previously received PCV13 or PCV15.

Note:

PPSV23 is not indicated for persons who previously received PCV20. For those who only received PPSV23, the CDC's ACIP recommends PCV15 or PCV20 at least one year after the most recent PPSV23 dose. For persons who received PCV13 with or without PPSV23, the CDC recommends PPSV23;

Adults 65 years of age or older

PCV15 or PCV20 for all adults 65 years of age or older.

Note:

If PCV15 is used, this should be followed by a dose of PPSV23 at least 1 year later;

PPSV23 for adults aged 65 years or older who previously received PCV13 or PCV15.

Note:

For adults 65 years or older who have only received PPSV23, CDC recommends a dose of PCV15 or PCV20 administered at least 1 year after the most recent PPSV23 vaccination.

Footnote1

* Risk conditions include:

alcoholism

cerebrospinal fluid leak

chronic heart disease, including congestive heart failure and cardiomyopathies

chronic liver disease

chronic lung disease, including chronic obstructive pulmonary disease, emphysema, and asthma

chronic renal failure or nephrotic syndrome

cigarette smoking

cochlear implant

congenital or acquired asplenia

congenital or acquired immunodeficiency (i.e., B- [humoral] or T-lymphocyte deficiency, complement deficiency, phagocytic disorder [excluding chronic granulomatous disease])

diabetes mellitus

generalized malignancy

HIV infection

Hodgkin disease

iatrogenic immunosuppression, including long-term systemic corticosteroids and radiation therapy

leukemia

lymphoma

multiple myeloma

sickle cell disease or other hemoglobinopathies

solid organ transplant (CDC, 2023b).

Footnote2

** Risk conditions include:

cerebrospinal fluid leak

chronic heart disease

chronic kidney disease (excluding maintenance dialysis and nephrotic syndrome, which are included in immunocompromising conditions)

chronic liver disease

chronic lung disease (including moderate persistent or severe persistent asthma)

cochlear implant

diabetes mellitus

immunocompromising conditions (on maintenance dialysis or with nephrotic syndrome)

congenital or acquired asplenia or splenic dysfunction

congenital or acquired immunodeficiencies

diseases and conditions treated with immunosuppressive drugs or radiation therapy, including malignant neoplasms, leukemias, lymphomas, Hodgkin disease, and solid organ transplant

HIV infection; and

sickle cell disease and other hemoglobinopathies) (CDC, 2023a).

Experimental and Investigational

Aetna considers pneumococcal conjugate vaccines (PCV13, PCV15, and PCV20) and pneumococcal polysaccharide vaccine (PPSV23) experimental and investigational for other groups because its effectiveness for groups other than the ones listed in Section I (above) has not been established.