Current Pneumococcal Vaccination Recommendations: A Clinical Update

Streptococcus pneumoniae is a gram-positive, facultative anaerobic bacterium that commonly colonizes the respiratory tract in children.¹ It can be transmitted through droplets and direct contact, causing respiratory infections such as sinusitis, otitis, and pneumonia. When isolated from a normally sterile site, it can develop into invasive pneumococcal disease (IPD), such as bacteremia or meningitis.² In the US, before the COVID-19 pandemic, it was responsible for 100,000 hospitalizations per year of non-invasive pneumonia and 30,000 cases per year of IPD.³

Numerous risk factors for developing IPD have been identified, which include younger or older age, diabetes, chronic heart and lung diseases, tobacco or alcohol use, immunodeficiency, malignancy, and immunosuppressive therapy. These groups experience IPD at higher rates compared to the general population (17.2 cases versus 13.2 cases per 100,000) and with higher mortality rates (2.7 deaths versus 1.8 deaths per 100,000).⁴ Racial disparities have also been identified, with more Black adults experiencing IPD at younger ages (55-59 years) and having longer hospitalizations.

Pneumococci are classified into serotypes based on the complex polysaccharides that encapsulate them.¹ These capsules serve as major virulence factors by aiding in escape from the immune system and causing invasive disease. While over 100 pneumococcal serotypes have been identified as of 2020, only 24 serotypes accounted for up to 75% of IPD in 2018-2019.5 Thus, vaccines have been designed to cover these most common serotypes by eliciting immunogenic responses to specific capsular polysaccharide and protein antigens.

There are two vaccine strategies for pneumococcal disease.¹ The pneumococcal polysaccharide vaccine (PPSV) induces B-cell and plasma cell response via a T-cell independent pathway, which does not produce serotype-specific memory B-cells and is poorly immunogenic in young children. In contrast, the pneumococcal conjugate vaccine (PCV) uses a genetically detoxified diphtheria toxin carrier protein to stimulate a T-cell dependent response, which facilitates memory B-cell formation. There are currently 3 PCVs and 1 PPSV available in the US.

Guidelines for pneumococcal vaccination are published by the Centers for Disease Control and Prevention based on recommendations from the Advisory Committee on Immunization Practices (ACIP).^3-5 These recommendations predominantly focus on the elderly and immunocompromised populations. Randomized controlled trials of these vaccines have reported efficacy of 30-70% in protecting adults against vaccine-type IPD. Despite these successes, numerous challenges remain. Although effective, vaccines have led to a rise in non-vaccine-targeted IPD, especially in unvaccinated adults.¹ Additionally, pneumococcal vaccination rates remain suboptimal.³ While up to 70% of adults 65 years and older receive the recommended vaccines, only 37% of eligible, at-risk adults aged 50-64 years were vaccinated according to 2022 data. Vaccination rates were highest for non-Hispanic white adults and lowest for Hispanic populations. Lack of awareness and vaccine hesitancy both contributed to low vaccine uptake. A cross-sectional survey of vaccine-eligible adults between 19-64 years of age in Tennessee found that only 19% were offered the pneumococcal vaccine.⁶

The same survey reported the most common reasons for vaccine hesitancy were being unaware of benefits (36%), fear of needles (29%), concern about side effects (28%), and exposure to negative media (19%). Variables that encouraged pneumococcal vaccination included recommendations from healthcare providers or government, influence from inner social circle, perceptions of safety and benefit, and information prompts such as brochures.⁷ Pharmacists can play important roles in identifying and overcoming these barriers by promoting pneumococcal vaccination rates in immunocompromised patients. In fact, pharmacy-driven vaccination protocols have improved the accuracy and consistency of pneumococcal vaccinations in hospitalized patients.^8,9

Pneumococcal Vaccines in the US

Pneumococcal vaccines have played crucial roles in preventing IPD, and they continue to evolve in response to changes in epidemiology and population needs. The first vaccine licensed in the United States was the 14-valent PPSV.¹ This was later replaced by the PPSV23 (named so for covering 23 serotypes), which continues to be the only PPSV product available today. The first PCV product, Prevnar7®, was released in 2007 and contained 7 serotypes. As the incidence of non-vaccine-targeted IPD cases increased, Prevnar13® became licensed to cover more serotypes, which has now been replaced with PCV15, PCV20, and PCV21.¹⁰ Today, there are 4 approved pneumococcal vaccination products in the US (Table 1), all of which are inactivated.^11-14

The most common side effects of pneumococcal vaccines are local and systemic reactions.^11-14 All vaccines are administered intramuscularly. Therefore, local injection-site reactions, such as pain, swelling, and erythema, are the most frequently reported events in up to 80% of recipients. Systemic reactions may also occur in up 40% within 1-2 days of injection and last 1-3 days. These reactions include fatigue, myalgia, headache, and pyrexia. In general, these reactions are mild to moderate, self-limiting, and may be managed with supportive care (reassurance, cool compresses, antipyretic and analgesic medications).¹⁵ Serious adverse events (SAE) occur in less than 1-2% of recipients at rates comparable to those reported in control groups.^11-14

Although concern for Guillain-Barré syndrome (GBS) has been raised, studies have not found increased rates after pneumococcal vaccines.^16,17 Post-marketing reports to the Vaccine Adverse Event Reporting System (VAERS) after PCV20 administration showed a low rate of GBS at 0.7 cases per million doses distributed.⁴ Additionally, although Centers for Medicare and Medicaid data showed a statistically significant signal for GBS after PCV20 administration, this difference was no longer significant after chart review confirmation of diagnostic codes.

Table 1. Overview of Vaccine Products^11-14

Figure 1. Serotypes^b,c Included in Pneumococcal Vaccines³

PCV15¹¹

This is a 15-valent conjugate vaccine that contains 2 additional serotypes beyond those covered by PCV13: 22F and 33F. Randomized-controlled trials have demonstrated improved immunologic responses to most serotypes compared to the PCV13 at 30 days, with no increase in SAE (2.5% and 2.4%, respectively). There were no vaccine-related SAE in the PCV15 arm. Most frequently reported reactions included injection site reaction (82%), fatigue (34%), and myalgia (29%).

PCV20¹²

This product is a conjugate vaccine with 7 serotypes in addition to the PCV13 and covers strains responsible for 56% of cases of IPD. Clinical trials have shown comparable immunogenicity in vaccine-naïve and exposed adults at 30 days after administration. The incidence of SAE was 1.5% with PCV20 versus 1.8% with controls, with no SAE related to the vaccine. The most common side effects were injection site pain (55%), myalgia (39%), fatigue (30%), and headache (22%), with median onset of 0-1 days after administration and duration 1-2 days.

PCV21¹³

This is a conjugate vaccine containing 21 serotypes responsible for 80% of IPD between 2018-2022, including 8 new serotypes not covered by other vaccines but cause 20-30% of cases. Notably, PCV21 does not include serotype 4, which the other licensed vaccines do contain. The incidence of IPD caused by serotype 4 has declined dramatically since the introduction of childhood pneumococcal vaccination. However, high prevalence (≥30%) remains in certain populations in the western United States, including Alaska, Colorado, Navajo Nation, New Mexico, and Oregon. Infected hosts are typically under 65 years of age without vaccination against serotype 4 and with underlying risk factors of alcoholism, chronic lung disease, smoking, unhoused, or injection drug use.

Phase 2 and 3 trials have demonstrated similar or higher immunogenicity of PCV21 at 30 days compared to other licensed vaccines in immunocompetent adults 50 years and older, both vaccine-naïve and previously vaccinated. Pooled safety data from 4 clinical trials of over 6,000 patients reported adverse events in 63.3% of PCV21 recipients, versus 63.0% in comparator vaccines (PCV15, PCV20, or PPSV23). The most reported adverse reactions included injection site events (55.6% vs 54.5%), fatigue (27.1% vs 23.7%), headache (18.4% vs 15.5%), and myalgia (11.3% vs 7.5%). Serious adverse events occurred in 1.5% versus 2%. This included two PCV21-related adverse events, bronchospasm and cellulitis, that both resolved.

PPSV23¹⁴

This is the only polysaccharide vaccine available. It covers an additional 39% of pneumococcal strains causing IPD compared to the PCV13. Studies have demonstrated 60-70% effectiveness in preventing IPD caused by the covered serotypes. Immune response occurs within 2-3 weeks. However, nonresponse to specific serotypes included in this vaccine may contribute to vaccine failure in some elderly adults.¹⁸ The most common reactions included injection side pain (60%), headache (18%), fatigue (13%), and myalgia (12%).

2024 ACIP Recommendations for Pneumococcal Vaccination

Figure 2. Timeline of pneumococcal vaccination recommendations^1,3-6,19,20

The ACIP has made significant updates to pneumococcal vaccination recommendations in the past several years based on approvals of higher-valency PCVs and the shifting epidemiology of IPD.²⁰ The initial introduction of childhood vaccines decreased the incidence of IPD in older adults, but has resulted in an increasing incidence of non-vaccine-targeted infections.¹⁹ In 2021, the PCV20 alone or PCV15 followed by PPSV23 were recommended in place of the PCV13. More recently, ACIP lowered the vaccination age for older adults to 50 years and older and streamlined the classifications of high-risk populations.⁴ The current guidance summarized below classifies patients based on age, risk factors, and prior pneumococcal vaccination history.

Pneumococcal vaccines may be given with other non-pneumococcal vaccines on the same day.²¹ Vaccines should be administered with separate syringes at different sites. However, pneumococcal vaccines should not be given on the same day as other pneumococcal vaccines. If administering both PCV and PPSV23, PCV should be given first, followed by PPSV23 at least 1 year after (or 8 weeks for adults with immunocompromising conditions, cochlear implant, or cerebrospinal fluid leak). If PPSV23 is inadvertently given first, patients should wait at least 1 year prior to receiving PCV15. Additionally, patients who have experienced IPD should still receive vaccination, as vaccines protect against multiple serotypes and provide additional protection against future infections.

Figure 3. Current Guidance on Pneumococcal Vaccination Recommendations⁴ Group 1: All adults aged 50 years and older⁴

Figure 4. Current Guidance on Pneumococcal Vaccination Recommendations⁴ Groups 2: Ages 18-49 with specific conditions, increasing risk of IPD⁴ Cochlear implant or cerebrospinal fluid leak

Figure 5. Current Guidance on Pneumococcal Vaccination Recommendations⁴ Groups 3: Ages 18-49 with specific conditions, increasing risk of IPD⁴ Immunocompromising conditions

Figure 6. Current Guidance on Pneumococcal Vaccination Recommendations⁴ Groups 5: Ages 18-49 with specific conditions, increasing risk of IPD⁴
Other chronic health conditions

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