Knock Out Pneumococcal Disease: Understanding Vaccination Recommendations

Streptococcus pneumoniae can cause medical issues as benign as ear infections and as serious as meningitis.

Pneumococcal disease may be spread from person to person via respiratory secretions and other routes. Some individuals may even be chronic “carriers” of the bacteria, even though they do not experience sickness.¹

Although treatment and prevention of pneumococcal disease through vaccination is an established part of pediatric care, the risk of infection and complication does not cease to exist at adulthood.

In 2012, S. pneumoniae was responsible for 4000 deaths, primarily in adults. In fact, pneumococcal disease kills more individuals in the United States each year than all other vaccine-preventable diseases combined.²

Even with appropriate antibiotics and medical management, the total pneumococcal bacteremia case-fatality rate is around 15% in adults and as high as 60% in the elderly.³ Although healthy adults are unlikely to contract serious infections caused by S. pneumonia, patients older than 65, those with various health conditions (eg, chronic kidney disease, obstructive lung diseases, HIV/AIDS) and those with certain lifestyle factors (eg, smoking, residence in a long-term care facility) are at an increased risk of developing severe pneumococcal disease.⁴

Despite the availability of modern medicine, it should be recognized that these infections may be serious, so disease prevention should be prioritized. There are at least 90 types of pneumococcal bacteria known to exist, making vaccination an even more important aspect of patient care.¹

Because of the high number of pneumococcal strains and increased mortality rate, vaccination has been identified as the best way to prevent the disease. Pneumococcal immunization recommendations have changed multiple times in previous years, but the rationale behind the new recommendations may not be clearly understood.

Vaccine Development and History

The first pneumococcal vaccine was licensed in 1977 and protected against 14 bacteria. In 1983, the 14-valent polysaccharide vaccine was replaced with the 23-valent polysaccharide vaccine [PPSV23 (Pneumovax 23)] that we are familiar with today, which contains 23 pneumococcal serotypes.⁴

In 2000, the first pneumococcal conjugate vaccine [PCV7 (Prevnar)] was marketed in the United States. This conjugate vaccine contained 7 serotypes of S. pneumoniae.

Finally, in 2010, PCV13 (Prevnar 13) was developed, adding 6 additional serotypes to PCV7. Currently, PCV13 is the recommended conjugate vaccine.

The only serotype contained in PCV13 that is not covered by PPSV23 is 6A.⁴ The 13 serotypes covered by PCV13 account for most of the serotypes involved in invasive pneumococcal disease.

Originally, PCV13 was only indicated for children, but in December 2011, the FDA licensed PCV13 for prevention of pneumonia and invasive pneumococcal disease in adults aged 50 years or older.⁴ The adult use of the vaccine was granted under the FDA’s accelerated approval pathway based on immunogenicity studies that compared antibody responses to PCV13 with antibody responses to PPSV23.

Given the high proportion of invasive pneumococcal disease caused by the serotypes found in PPSV23, improved protection is anticipated through use of both PCV13 and PPSV23 in series.

When Does a Patient Need PCV13 and PPSV23?

Many patients will be eligible to receive both the polysaccharide and conjugate vaccines.

When this situation is encountered, PCV13 should be administered before PPSV23, if at all possible. It has been observed that PPSV23 blunts the immune response to conjugate vaccines given after PPSV23, especially in adults.

A randomized trial was performed in the United States and Sweden involving adults aged 70 years or older with the objective of demonstrating PCV13 was at least as immunogenic as PPSV23. Immunogenic response was measured by opsonophagocytic activity titers.

In this study, it was discovered that when PCV13 was given after PPSV23, the response was statistically significantly lower for all 13 serotypes compared to the initial PCV13 dose, indicating that PPSV23 hinders the response to subsequent PCV13.⁵

Another notable study compared immunogenicity and safety of PCV7 and PPSV23 in adults aged 70 years or older who were not previously vaccinated against pneumococcal disease. It was noted that when the conjugate vaccine was administered after the polysaccharide vaccine, antipolysaccharide and opsonophagocytic activity immune responses were reduced.⁶

Likewise, in 2011, yet another study reported that administration of PPSV23 prior to PCV7 significantly attenuated antibody concentration compared with PCV7 alone in those aged 50 to 70 years.⁷

Based on all of this evidence, it is most beneficial for patients who are candidates for both pneumococcal vaccines to receive PCV13 followed by PPSV23.

Although it is well defined that PCV13 is most beneficial when administered before PPSV23, when it comes to choosing an interval between PCV13 and subsequent PPSV23, clinical efficacy data is not available to aid in decision-making. Although immunogencity studies are available, it is difficult to compare evidence across them.

In examining intervals of 2, 6, and 12 months as well as 3 to 4 years between the administration of PCV13 and PPSV23, longer intervals seemed to improve response and shorter intervals seemed to increase reactogenicity.^8,9

Current vaccine administration recommendations from the US Centers for Disease Control and Prevention (CDC) are as follows:

• For those aged 65 years or older who have not previously received any pneumococcal vaccine, give PCV13 followed by PPSV23 6 to 12 months later.
• For those aged 19 to 64 years at high risk of pneumococcal disease, give PCV13 followed by PPSV23 at least 8 weeks later.
• For adults who have already received PPSV23, wait 12 months before giving PCV13.³

Interestingly, at a CDC Advisory Committee on Immunization Practice (ACIP) meeting in July 2015, it was proposed that the interval between PCV13 and subsequent PPSV23 be prolonged to 12 months (rather than 6 to 12 months) for those aged 65 years or older in order to simplify the vaccine schedule. This change would make the intervals between PPSV23 followed by PCV13 and PCV13 followed by PPSV23 the same.¹⁰

The Evidence for Pneumoncoccal Vaccination

Disease Prevention

PPSV23 and PCV13 have both demonstrated evidence in reducing the incidence of pneumococcal-related diseases. PPSV23’s strongest evidence is against invasive pneumococcal disease, as the vaccine is shown to reduce its incidence by approximately 50% to 80%.¹²

The polysaccharide vaccine provides broad coverage through inclusion of 23 serotypes, 11 of which are not represented in PCV13. These 11 additional serotypes are responsible for 38% of invasive pneumococcal disease in adults aged 65 years or older.¹³ However, PPSV23 has demonstrated little evidence of its effectiveness against pneumococcal pneumonia.

A 3-year prospective cohort study following 27,204 individuals aged 60 years or older showed the risk of community acquired pneumonia was not substantially lowered in those receiving PPSV23 than those receiving placebo (HR 0.94 [95% CI 0.80-1.12]; P=0.51).¹⁴ Although studies have not shown a significant improvement in decreasing pneumonia, the decreased incidence of invasive pneumococcal disease exhibits sufficient benefit to continue to recommend administration of this broad-coverage vaccine.

Despite the fact that PCV13 does not contain as many serotypes as PPSV23, it does have increased immunogenicity for 8 of the 12 overlapping serotypes, as well as coverage of one additional serotype: 6A.¹⁵ But what does this mean in terms of clinical significance?

In 2012, the FDA required the manufacturer of PCV13 to complete an efficacy study on the prevention of pneumococcal pneumonia in patients aged 65 years or older. This led to the development of the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA), which assessed 84,496 participants in this age group and showed 45.6% (95% CI 21.8-62.5%; P=0.0006) efficacy against first episode of vaccine-type community-acquired pneumonia.¹⁶

In June 2014, CAPiTA led ACIP to recommend PCV13 in addition to PPSV23 for adults aged 65 years or older.¹³ Although PCV13 does not include as many serotypes as PPSV23, it does have evidence for the prevention of pneumonia.

Another proven benefit of PCV13 in terms of disease prevention is producing indirect immunity against pneumococcal diseases in all age groups in the United States.

A study conducted in 2013 investigated the incidence of invasive pneumococcal disease before and after the introduction of PCV13 using data from the Active Bacterial Core surveillance. It found that within 3 years of introducing PCV13, all adult age groups experienced a 12% to 32% reduction in invasive pneumococcal disease and a 58% to 72% reduction in invasive pneumococcal disease caused by serotypes specific to PCV13, as compared with PCV7.¹⁷

To better understand these data, it is important to examine the character of each vaccine.

Mechanisms of Coverage

PPSV23 is composed of capsular polysaccharides, or long chains of sugar molecules that make up the cell wall of certain bacteria. Polysaccharide vaccines induce antibodies via T-cell-independent mechanisms, meaning these vaccines do not use T-cells to produce an antibody response.

Immune systems—especially immature systems—find it difficult to create antibodies for polysaccharides antigens. Therefore, children younger than 2 years do not respond well to this type of vaccine.¹⁸

PCV13, the newer of the 2 available vaccines, is approved for vaccination of children and certain adults.

In the late 1980s, the process of conjugation was discovered. It involves chemically combining a polysaccharide with a protein molecule to improve the body’s immune response to the antigen.¹⁸

PCV13 converts the body’s immune response from T-cell-independent to T-cell-dependent response, thus allowing the vaccine to elicit immune response in infants. The T-cell-dependent response is superior to the T-cell independent response in that it lasts longer, produces a booster response at re-exposure, and reduces nasopharyngeal carriage of S. pneumonia in children.¹³

Consequently, PCV13 is effective in children younger than 2 years and is associated with indirect herd protection.

Overall, both vaccines have advantages and disadvantages, leading to the current recommendation for administration of both vaccines in certain patient populations.

Pneumococcal Vaccination in the Future

The future of pneumococcal vaccines is uncertain, especially with herd immunity continuing to increase protection of patients aged 65 years or older. In 2018, ACIP will re-evaluate the necessity of elderly patients receiving PCV13.

Important areas of future research are the duration of protection of PCV13 and the need for revaccination. These will be of particular interest if PCV13 continues to be routinely recommended for older adults by ACIP in 2018.

Another important area of research in relation to pneumococcal vaccines involves monitoring changes in specific serotypes causing pneumococcal diseases. This continuous monitoring will help in the formulation of future conjugate vaccines.

The Program for Appropriate Technology in Health is collaborating with various institutions to develop conjugate vaccines that target different serotypes, especially those prevalent in underdeveloped countries.¹⁹ However, developing and testing new PCV serotypes is costly and complicated, which necessitates other strategies for pneumococcal coverage.

One unique strategy currently being investigated to overcome issues associated with polysaccharide-based vaccines is adding pneumococcal proteins to the vaccine, such as pneumolysin toxoid and histidine-triad protein.²⁰ An additional serotype-independent strategy involves the addition of pneumococcal surface protein and a choline-binding protein, which are capable of eliciting an antibody-based immunity.²¹

Another technique used in an attempt to increase coverage of pneumococcal vaccines is the use of killed whole pneumococcal cells. Preliminary data on the use of whole cells shows protection against nasopharyngeal colonization and invasive disease.²²

There is hope that these novel vaccine approaches will produce positive outcomes in immunogenicity and potentially serve to prevent disease caused by pneumococcal strains not covered by the currently available vaccines. Until that time, pharmacists should encourage patients who meet the criteria for pneumococcal vaccination to receive their immunizations and educate them and other health care professionals on the rationale behind the immunization schedule to help substantially minimize the impact of one of the most common pathogens causing infection in the adult population.

This article was collaboratively written with Mary Katherine Stuart and Sarah Mills, who are both 2016 PharmD Candidates at Auburn University’s Harrison School of Pharmacy.

References

• US Centers for Disease Control and Prevention. About pneumococcal disease. http://www.cdc.gov/pneumococcal/about/index.html. June 10, 2015.
• US Centers for Disease Control and Prevention. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine for adults with immunocompromising conditions: recommendations of the Advisory Committee on Immunization Practices. MMWR. 2012;61(40):816-9.
• US Centers for Disease Control and Prevention. Prevention of pneumococcal disease: recommendation of the Advisory Committee on Immunization Practices. MMWR. 1997 Apr 4;46(8):1-24.
• Pneumococcal vaccines (PCV13 and PPSV23). http://www.immunize.org/askexperts/experts_pneumococcal_vaccines.asp. July 2, 2015.
• Jackson LA, Gurtman A, van Cleeff M, Jansen KU, Jayawardene D, Devlin C, Scott DA, Emini EA, Gruber WC, Schmoele-Thoma B. Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine compared to a 23-valent pneumococcal polysaccharide vaccine in pneumococcal vaccine-naive adults. Vaccine. 2013 Aug;31(35):3577-84.
• De Roux A, Thoma BS, Siber GR, et al. Comparison of pneumococcal conjugate polysaccharide and free polysaccharide vaccines in elderly adults: conjugate vaccine elicits improved antibacterial immune responses and immunological memory. Clin Infect Dis. 2008;46: 1015-23.
• Lazarus R, Clutterbuck E, Yu LM, et al. A randomized study comparing combined pneumococcal conjugate and polysaccharide vaccination schedule in adults. Clin Infect Dis. 2011;52: 736-42.
• Greenberg RN, Gurtman A, Frenck RW, Strout C, Jansen KU, Trammel J, Scott DA, Emini EA, Gruber WC, Schmoele-Thoma B. Sequential administration of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine in pneumococcal vaccine-naïve adults 60-64 years of age. Vaccine. 2014 Apr;32(20):2364-74.
• Kobayashi M. Intervals between PCV13 and PPSV23 vaccines: evidence supporting currently recommended intervals and proposed changes. Program and abstracts of the Advisory Committee on Immunization Practices meeting; June 24-25, 2015; Atlanta, Georgia.
• Tomczyk S, Bennett NM, Stoecker C, et al. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among adults aged ≥65 years: recommendations of the Advisory Committee on Immunization Practices. MMWR. 2014;63:822-825.
• Musher DM, Rueda AM, Nahm MH, Graviss EA, Rodriguez-Barradas MC. Initial and subsequent response to pneumococcal polysaccharide and protein-conjugate vaccines administered sequentially to adults who have recovered from pneumococcal pneumonia. J Infect Dis. 2008;198(7):1019.
• Organization WH. 23-valent pneumococcal polysaccharide vaccine. WHO position paper. Wkly Epidemiol Rec. 2008;83:373—84.
• Pilishvili T, Bennett NM. Pneumococcal disease prevention among adults: Strategies for the use of pneumococcal vaccines. Vaccine. 2015;33 Suppl 4:D60-5.
• Vila-corcoles A, Ochoa-gondar O, Rodriguez-blanco T, De diego C, Satue E. Ineffectiveness of pneumococcal vaccination in cardiovascular prevention: the CAPAMIS study. JAMA Intern Med. 2013;173(20):1918-20.
• Jackson LA, Gurtman A, van Cleeff M, Jansen KU, Jayawardene D, Devlin C, Scott DA, Emini EA, Gruber WC, Schmoele-Thoma B. Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine compared to a 23-valent pneumococcal polysaccharide vaccine in pneumococcal vaccine-naive adults. Vaccine. 2013 Aug;31(35):3577-84. (D)
• Van werkhoven CH, Bonten MJ. The Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA): what is the future of pneumococcal conjugate vaccination in elderly? Future Microbiol. 2015;10:1405-13.
• Moore MR, Link-Gelles R, Schaffner W, et al. Effect of use of 13-valent pneumococcal conjugate vaccine in children on invasive pneumococcal disease in children and adults in the USA: analysis of multisite, population-based surveillance. Lancet Infect Dis. 2015;15(Mar (3)):301—9.'
• US Centers for Disease Control and Prevention. Principles of vaccination. http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/prinvac.pdf. September 8, 2015. Accessed December 13, 2015.
• Assaad U, El-masri I, Porhomayon J, El-solh AA. Pneumonia immunization in older adults: review of vaccine effectiveness and strategies. Clin Interv Aging. 2012;7:453-61.
• Leroux-roels G, Maes C, De boever F, Traskine M, Rüggeberg JU, Borys D. Safety, reactogenicity and immunogenicity of a novel pneumococcal protein-based vaccine in adults: a phase I/II randomized clinical study. Vaccine. 2014;32(50):6838-46.
• Frey SE, Lottenbach KR, Hill H, et al. A Phase I, dose-escalation trial in adults of three recombinant attenuated Salmonella Typhi vaccine vectors producing Streptococcus pneumoniae surface protein antigen PspA. Vaccine. 2013;31(42):4874-80.
• Lu YJ, Leite L, Gonçalves VM, et al. GMP-grade pneumococcal whole-cell vaccine injected subcutaneously protects mice from nasopharyngeal colonization and fatal aspiration-sepsis. Vaccine. 2010;28(47):7468-75.