Dr. Parvaiz Koul delivers a primer on pneumococcal vaccination along with recent changes made by ACIP to the vaccination plan and schedule for adults and subsequent adaptations of the guideline changes made by Indian associations.

---

Lower respiratory infections are a major cause of morbidity and mortality. According to the Global Burden of Disease (GBD) 2016 estimates, lower respiratory tract infections (LRI), defined as pneumonia or bronchiolitis, were the leading cause of mortality and morbidity worldwide, the prevalence being the highest in Sub-Saharan Africa, South Asia, and Southeast Asia. Approximately 2.38 million deaths resulted from LRI in 2016. Streptococcus pneumoniae (Pneumococcus) emerged as the leading cause of LRI morbidity and mortality globally, contributing to more deaths compared to all other aetiologies combined in 2016 (1,189,937 deaths).

Pneumococcal diseases are broadly classified into invasive and non-invasive forms:

• Non-IPD includes sinusitis, acute otitis media, and non-bacteremic community-acquired pneumonia (CAP)
• Invasive pneumococcal disease (IPD) is diagnosed when the pathogen is identified in normally sterile body fluids like CSF, blood, and pericardial fluid of an affected individual leading to bacteremia, meningitis, etc

Other manifestations of pneumococcal infection include meningitis, bacteremia of undetermined cause, and otitis media.

---

S. pneumoniae is a gram-positive bacterium with a characteristic polysaccharide capsule which determines its pathogenicity and exists in >90 serotypes, that vary in pathogenicity, and incidence according to geographical and age distribution. The pathogen colonises the nasopharynx and through the transmission to the lower respiratory tract, leads to the development of pneumonia. Various risk factors that predispose to pneumococcal disease include factors like underlying chronic lung, heart or liver disorders, immunocompromised states, anatomical or functional hyposplenism, history of meningitis or cochlear implants, etc. About 20-30% of CAP in India has a pneumococcal etiology.

Pneumococcal vaccination is an important preventive health care measure that has substantially reduced the burden of pneumococcal disease in vaccinated individuals and in the population in developed nations. It is indicated for adults with risk factors for development of pneumococcal disease or its adverse outcomes. While pneumococcal vaccination is a routine part of infant and childhood immunisation schedules worldwide, it has only recently been introduced in the childhood immunisation program in India, in a phased manner.

---

Types of pneumococcal vaccines:

There are 2 types of vaccine against pneumococcus, the pneumococcal polysaccharide vaccine (PPSV) and the pneumococcal conjugate vaccine (PCV). Both of these are based on the capsular pneumococcal polysaccharide antigen. Since more than 90 serotypes have been identified, a single vaccine containing all the serotypes is impossible and hence vaccines have been developed against the common serotypes that cause human disease.

Pneumococcal polysaccharide vaccine (PPSV)

PPSV is the most widely available vaccine and is composed of partially purified pneumococcal capsular polysaccharides against the common 23 pathogenic serotypes of pneumococcal capsular polysaccharide. These serotypes would be responsible for 85 to 90 percent of cases of pneumococcal disease in the West but now cause only about 50 to 60 percent of such cases in adults. Data about the serotypes of pneumococci causing disease in Indian adults are scant.

Pneumococcal conjugate vaccine (PCV)

In order to enhance the immunogenicity of polysaccharide pneumococcal vaccines, conjugate vaccines have been developed wherein the polysaccharide antigens are joined to an immunogenic protein carrier (such as tetanus or diphtheria toxoid). This results in an enhanced immunological response, characterised by induction of both a B- and a T-cell-dependent response and a memory B-cell response to a booster dose of the vaccine.

Pertinently, young children do not respond to the polysaccharide antigens, but conjugation to protein helps the immature immune system in children to recognise and process the polysaccharide antigens, leading to production of antibody. Conjugated polysaccharides also stimulate mucosal immunity, which eradicates nasopharyngeal carriage. Since children are the principal reservoir for pneumococci in the population, the widespread use of PCV in this population in the developed countries has led to a dramatic reduction in incidence of disease caused by vaccine serotypes in adults.

PCV13 contains 13 capsular types and is the most widely used formulation. PCV is also used in in adults at high risk for pneumococcal infection or its complications, even as the scientific basis is less robust. The development of a 20-valent pneumococcal conjugate vaccine is also underway.

---

Proof of effectiveness in prevention of pneumococcal disease

Pneumococcal polysaccharide vaccine

Several randomised trials have demonstrated the vaccine's efficacy in reducing invasive pneumococcal disease (IPD) in healthy adults, caused by serotypes contained in the vaccine. In a meta-analysis of 18 randomised trials evaluating over 64,500 individuals, PPSV reduced the risk of IPD in otherwise healthy individuals with greater reduction of vaccine-type serotype-related disease. PPSV also was associated with a reduction in invasive as well as non-invasive pneumococcal pneumonia with a reduction in pneumonia of any cause in low-income countries.

The degree of protection provided by pneumococcal polysaccharide vaccines is still debated among experts and varies among studies. Some studies suggest that PPSV protects against invasive (i.e., bacteremia, meningitis, bacteremic pneumonia) but not non-invasive pneumococcal disease, which seems biologically implausible. However, some studies have failed to demonstrate efficacy for prevention of disease or mortality.

The possible reasons of the contrasting results could be rarity of the outcomes being assessed, inherent difficulties in accurate microbiologic diagnosis of pneumococcal aetiology, and use of non-validated diagnostic tests. Expectedly studies with more specific endpoints (eg, serotype-associated IPD) have been more likely to demonstrate vaccine efficacy than studies with less specific endpoints (eg, all-cause pneumonia or mortality).

A serious concern is that vaccine efficacy is diminished in those who are at greatest need for vaccination (e.g. older adults, immunocompromised patients). In one case-control study evaluating >2000 patients, PPSV was 85 to 90% effective in preventing IPD in adults <55 years of age. However, the efficacy declined with increasing age and no benefit was observed 5-years after vaccination among persons >80 years old. Among immunocompromised patients, vaccine efficacy varies with the degree and type of immunosuppression. But, there is some benefit observed even among patients with significant humoral immune deficits (e.g. asplenia) and as such is recommended.

Pneumococcal conjugate vaccine

Conjugation with the protein component (like diphtheria toxin) represented an important advance in the development of pneumococcal vaccine as the conjugate vaccine was able to induce a more robust immune response with involvement of the T-cells and ability to induce release of high affinity IgG antibodies. The routine use of PCV in children led to change in the serotype prevalence as well as development of ‘herd immunity’.

In one of largest vaccine trials, CAPiTA trial that involved about 85,000 individuals, PCV 13 demonstrated 46% efficacy of PCV13 against vaccine-type pneumococcal pneumonia, 45% efficacy against vaccine-type nonbacteremic pneumococcal pneumonia, and 75 percent efficacy against vaccine-type invasive pneumococcal disease. Efficacy persisted for the duration of the trial (mean follow-up four years). Given the dramatic reduction in IPD, observed in adults following the routine use of PCV in children in the United States due to the herd effect  the added benefit of vaccinating adults ≥65 years may be marginal.

An untoward effect of the widespread use of pneumococcal conjugate vaccines has been the emergence of "replacement strains," that are non-vaccine pneumococcal serotypes that have appeared as colonisers of the nasopharynx and replacement strains of pneumococcal disease, e.g. S. pneumoniae type 19A (not included in PCV7) emerged as the commonest strain of pneumococcal disease after the universal vaccination with PCV7 in the United States. Similarly, other non-vaccine serotypes have greatly increased in frequency after the introduction of PCV13. Table 1 shpws the serotypes of pneumococcus in the 2 available vaccines.

Serotypes covered in PPSV 23 and PCV-13

Type of vaccine	Serotypes covered
PPSV 23	1,2, 3, 4, 5, 6B, 7F, 9N, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 20, 22F, 23F
PCV-13	1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F

---

Vaccination schedule for pneumococcal vaccination

Recently, the Advisory Committee for Immunization Practices (ACIP), USA rescinded its prior recommendation to vaccinate all adults ≥65 years old with both PCV13 and PPSV23. The committee now recommends PPSV23 for all patients in this age group and advises clinicians to engage in shared decision-making to determine whether PCV13 should be given in addition to PPSV23 for patients who otherwise lack an indication for dual vaccination (e.g. impaired splenic function, cochlear implant). The change in recommendation is based on the dramatic reduction in the incidence of infection with PCV13 serotypes that has resulted from universal childhood PCV13 vaccination. Thus,

• Vaccination with PCV is not recommended unless there is another indication for PCV (i.e. immunocompromise, asplenia, cerebrospinal fluid leak, cochlear implant, or history of invasive pneumococcal disease) and having not previously received the vaccine.
• For adults with certain chronic conditions that place them at higher risk for pneumococcal disease (i.e. chronic cardiac, lung, and/or liver disease, diabetes mellitus, smoking, and/or alcohol use disorder), a shared discussion is held between the patient and the care provider regarding the risks and benefits of PCV13 on an individual basis. The decision to vaccinate the individual with PCV is taken on the basis of this discussion.

Recommended schedule for pneumococcal vaccination

Age	Initial dose	Subsequent dose
Age 65 years or older (immunocompetent)
	1 dose PPSV	If PPSV 23 was administered prior to age 65years, administer 1 dose PPSV at least 5 years after previous dose
On shared-clinical decision	1 dose PCV13*	PPSV 1 year apart
Age 19-64 years or older with medical conditions
19 through 64 years with chronic medical conditions**	1 dose PPSV 23	At age 65 years or older, administer 1 dose PPSV23 at least 5 years after most recent PPSV23 (only 1 dose PPSV23 recommended at age 65 years or older)
Age 19 years or older with immunocompromising conditions***	1 dose PCV13 followed by 1 dose PPSV23 at least 8 weeks later	PPSV23 at least 5 years after previous PPSV23 At age 65 years or older, administer 1 dose PPSV23 at least 5 years after most recent PPSV23 (only 1 dose PPSV23 recommended at age 65 years or older)
Age 19 years or older with cerebrospinal fluid leak or cochlear implant	1 dose PCV13 followed by 1 dose PPSV23 at least 8 weeks later	At age 65 years or older, administer another dose PPSV23 at least 5 years after PPSV23 (only 1 dose PPSV23 recommended at age 65 years or older)

* based on shared clinical decision-making

** chronic heart (excluding hypertension), lung, or liver disease, diabetes), alcoholism, or cigarette smoking

*** congenital or acquired immunodeficiency [including B- and T-lymphocyte deficiency, HIV infection, complement deficiencies, phagocytic disorders, immunosuppressive drug use], chronic kidney disease, nephrotic syndrome, leukemia, lymphoma, Hodgkin disease, generalised malignancy, solid organ transplant, multiple myeloma) or anatomical or functional asplenia (including sickle cell disease and other hemoglobinopathies

---

Revaccination with PPSV 23

Advisory Committee on Immunization Practices (ACIP), recommends one PPSV23 revaccination dose (≥5 years after the first) for persons age 19 to 64 years with impaired splenic function and other immunocompromising conditions followed by a second revaccination dose once the individual reaches age 65 years (provided ≥5 years have elapse since the last). The ACIP does not recommend revaccination for any other at-risk population (e.g. those >65 years or those with CSF leaks or cochlear implants).

Revaccinating before five years have elapsed can blunt the immune response; this hyporesponsiveness is lost if more than five years have passed since the previous dose. Some organisations suggest checking pneumococcal antibodies to help guide the need for PPSV23 revaccination in high-risk patients. However the utility of antibody levels are unclear even as serum concentrations of 0.35 mcg/mL have been designated as protective for children.

Revaccination with PCV13 is not recommended for any age or risk group.

---

Interval between PCV and PPSV

Giving a pneumococcal conjugate vaccine (e.g. PCV13) prior to a polysaccharide vaccine (e.g. PPSV23) has the potential to enhance the immune response to the polysaccharide vaccine by stimulating memory B cells and priming the immune system. In contrast, giving a polysaccharide vaccine closely followed by a conjugate vaccine suppresses immune responses.

For patients who need both pneumococcal vaccines, PCV13 is ideally given first, followed by PPSV. In patients who are at high risk for pneumococcal infection, PPSV can be administered only eight weeks following the PCV dose. Extending the interval between the vaccinations for such cases with immunocompromise is unlikely to augment antibody development.

• For patients whose primary indication for vaccination is age ≥65 years, PCV13 first followed by PPSV23 ≥1 year later
• For adults who have received PPSV23 prior to PCV13, a ≥1-year interval is recommended between the two vaccines

---

Co-administration with influenza and other vaccines

Pneumococcal vaccine can be concomitantly used with other non-pneumococcal vaccines using different sites and different syringes.

---

Adverse effects, safety, and contraindications

Injection site reactions like pain, swelling and tenderness or induration can be seen in upto 20% cases. These generally resolve spontaneously in 3 to 4 days and may require NSAIDs. Some recipients develop systemic symptoms like fever, rigors, chills, myalgias, arthralgias, etc. These are generally mild and self-limiting.

---

Indian perspective

Pneumococcal vaccination in adults in India has traditionally been a rather neglected area. However, with the recognition of the morbidity and mortality associated with pneumococcal disease in the older adults and individuals with chronic comorbidities, a number of Indian physician bodies like the Geriatric Society of India, Association of Physicians of India, Indian Association for Occupational Health, Indian Diabetes Association, Indian Society of Nephrology, Indian Chest Society, etc have recommended use of pneumococcal vaccine for their patients and formulated policies for their patient groups.

The Indian recommendations vary from the recommendations of the Western counterparts like the ACIP, etc. with respect to the following:

1. Most of the societies have recommended pneumococcal vaccination beyond 50 years of age, instead of 65 years. This recommendation is supposed to be based on the fact the life expectancy of Indian adults has only recently been known to have reached 67 years in males and 70 years in females and the Ministry of Health and Family Welfare considers all individuals as ‘older adults’ at higher risk for disease. Some societies put forth an argument of vaccinating at a time when immunosenescence hasn’t set in.
2. PCV 13 continues to recommended as the first choice followed later by PPSV 23. This is based on the premise that since PCV has been introduced in children only recently and is being slowly rolled out across the country as a part of the Universal Immunization Program, the serotypes causing disease are likely to be the same that are contained in the PCV 13 and as such vaccination against those serotypes would be important till we reach a stage of near universal immunisation among children that would eventually result in serotype switching in the nasopharyngeal flora of Indian children.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

Dr. Parvaiz Koul is a Professor and Head, Pulmonary and Internal Medicine, Infectious Diseases/ Geriatrics, Srinagar.