The goal of this paper is to provide a narrative synopsis of the literature on the changes in pneumococcal vaccine guidelines in the USA over the last two decades. The goal was not to conduct a systematic review or meta-analysis of the epidemiology of pneumococcal vaccines. Our perspective is that considering the prevalence and risk factors for IPDs discussed above, the history and the evolvement of vaccines against IPDs, it would be more beneficial to explore the changes in vaccine schedules over the years and the reasons for these changes. Based on the literature, we pivot on the impact of vaccination against pneumococcal bacteria, as well as historical limitations, with regard to issues of public health concerns and provision of public health services. In addition, these areas have not been extensively reviewed in the past. We conclude with some prospects for future directions and areas of research in this area.

Whole Killed Pneumococcal vaccines: First-generation vaccines are live attenuated whole organisms or inactivated toxins, able to provoke innate immunity [9] . They are cheap, easy to produce, and induce long-term protection. More than a century ago, cases of Pneumococcal infection from Pneumococcus types 1, 2, and 3 were successfully challenged by inoculation with doses of killed Pneumococcal vaccines [4] . This followed an earlier study in 1891 when repeated inoculation with killed pneumococci, provided immunity against future attacks, using animal specimens, based on humoral immunity. In the USA, in 1917, varying doses of killed pneumococci were inoculated from infected subjects. Pneumococcal agglutination, protection from serum vaccines, and their adverse effects were studied. In 1944, polysaccharides from types 1, 2, 5, and 7 Pneumococcus were used in a clinical trial and showed significant reduction in types 2 and 7 pneumococcal infection [4] .

Limitations and drawbacks: Efficacy from killed, whole pneumococci could have been from other bacterial cell components apart from the polysaccharide antigen. Also, the incidence of non-vaccine type pneumonia was unchanged [4] .

In 1911, attempts to develop pneumococcal vaccines that would be efficacious against Strep. Pneumoniae began [1] . Despite antibiotic treatment with penicillin in the 1940s, patients still died within 4 days of treatment from pneumonia caused by this bacterium [1] [4] . By the 1960s, further attempts were made to develop a polyvalent vaccine against pneumococcal pneumonia [1] . The first pneumococcal vaccine and the first pneumococcal conjugate vaccine (PCV) were first licensed in the United States for use in 1977 and 2000, respectively. The first pneumococcal vaccine is no longer produced; however, it was a 14-valent capsular polysaccharide purified from fourteen distinct types of pneumococci. This vaccine was replaced by a 23-valent polysaccharide vaccine (PPSV23), also called Pneumovax 23, in 1983, made from serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, and 33F [1] .

The introduction of pneumococcal conjugate vaccine7 (PCV7) also called Prevnar7, the first PCV, in the US immunization schedule in 2000, saw a reduction in S. Pneumoniae antibiotic resistance, which further declined in children following the invention of PCV13 in 2010 [1] [8] . PCV7 also exhibited herd immunity in unvaccinated adults [10] . Before it replaced PCV7, serotypes of PCV13 (Prevnar13) were discovered to cause 61% of severe disease in under-fives, compared to 2% from PCV7 serotypes [1] . PCV7 and PCV13 have both caused a decline in invasive pneumococcal serotype infections in the pediatric population by 99% and 90%, respectively. PCV13 contains serotypes of PCV7 (7F), 1, 3, 5, 6A, 6B, 7F, 9V, 14, 18C,19A, 19F and 23F. PPSV23 is administered intramuscularly or subcutaneously by injection, while PCV13 is administered intramuscularly [1] . PCV15 and 20 are newly introduced vaccines in 2021, both sterile suspensions of polysaccharides from 15 and 20 serotypes respectively [2] [6] [11] . Both PCV15 and PCV20 are conjugated to CRM₁₉₇ [6] [10] [12] [13] .

This generation of vaccines is made of the pathogen’s subunit elements, recombinant proteins, non-protein antigens such as glycans, and the pathogen’s expressed immunogens [9] . These immunogens include several antigenic determinants and molecules of the different strains of the organism. Examples of second-generation vaccines are subunit, conjugated, and recombinant vaccines [9] , which includes all PCVs and the PPSV.

Composition and efficacy: The pneumococcal vaccines are conjugate subunit vaccines [5] . They are made from the chemical bonding of polysaccharides from the surface of the Pneumococcal bacteria to a protein molecule. This initiates a host B-cell response autonomous from T-helper cells, stimulating host immunity [5] . The average efficacy of PPSV is 84% [4] . Both PCV and PPSV vaccines do not contain any antibiotic, however, PPSV23 contains phenol as a preservative, and PCV13 has no preservatives. Whereas PCV13 has aluminum phosphate adjuvant and succinate buffer, PPSV23 has no adjuvant [4] [14] . It is an aseptic mixture of 13 capsular polysaccharides of S. pneumoniae, available in a single-dose injection [14] . PCV13 is chemically conjugated to a nontoxic variant of diphtheria toxin (CRM₁₉₇) [1] [4] [14] . The PPSV did not produce an immune response in children less than 2 years old [4] [15] . This poor immunogenicity was overcome by PCV7 through conjugation technology. PCV7 and 13 both provide herd immunity and similar adverse events records, however, PCV13 produces a better immune response in adults at one month post-vaccination and no difference after 12 months of vaccination respectively, in contrast to PPSV23 [4] [10] [15] . PCV13 has further shown cost-effectiveness in vaccine-preventable Pneumococcal disease in HIV-specific populations and in the general populations of adults over 50 years [4] .

In 2008, the World Health Organization (WHO) recommended the inclusion of PCVs in national immunization programs for those under five and above 65 years of age, as well as those with positive infection for human immunodeficiency virus (HIV) [7] . PCV7 was the only vaccine licensed for use and introduced into the US infant immunization schedule in 2000 before PCV10 and PCV13 were formulated, yet it was not quickly implemented in other countries due to its inflated cost [2] [7] . Before its first use in 2000, the incidence of IPDs was highest in under 2 years of age [8] . These IPDs included bacteremia, meningitis, community-acquired pneumonia, otitis media, and pneumonia with S. pneumoniae as the leading culprit, [1] [12] an annual incidence of 165 cases/100,000 children < 12 months of age and 203 cases/100,000 children 12 - 23 months of age [15] . It is estimated that worldwide use of PCVs will avoid 5.4 - 7.7 million deaths in children by 2030 [7] .

Prior to 2004, a surveillance study done in Massachusetts showed a significant increase in IPD due to serotype 19A [16] . It was also shown that serotype 19A was the most common cause of refractory acute otitis media in Rochester, New York, and acute mastoiditis and chronic sinusitis in hospitalized children at Texas Children’s Hospital in Houston [17] . These prompted the need to develop a second-generation PCV, a 13-valent vaccine contains capsular polysaccharides antigens of serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F. It was licensed and recommended for universal immunization of children less than two years and through age five years in 2010, due to its safety profile and immunogenicity [16] [17] . The simultaneous increase in non-vaccine serotypes (NVTs) did not affect the decline in IPDs covered by PCV13 serotypes [1] .

Limitations and drawbacks: Contemporary research has shown a decrease in efficacy of PPSV23 due to perseverance of serotypes (such as 3 & 19A) for which it does not offer good protection; decrease in PCV13 strains; and resulting evolution of strains (types 15A, 23B, 35 and 38) not covered by PPSV23 [4] . Thus, PPSV failed to immunize toddlers and infants, leading to production of conjugated pneumococcal vaccines. Following the introduction of PCVs, specifically PCV7, there was an increase in NVT pneumococcal infection, which were also resistant to antibiotics (for example, serotype 19A). This led to the introduction of PCV13 a second-generation PCV in 2010, to curb infections by serotypes not covered by PCV7 [1] [8] . PCVs do not protect against infections caused by NVTs and unencapsulated organisms [18] . PCV13 also does not cover serotypes of S. pneumoniae disease not in the vaccine [19] . Table 1 below summarizes pneumococcal vaccines and Table 2 summarizes PCV13 recommendations by the Advisory Committee Immunization Practices (ACIP).

Note: Abs = antibodies.

Note: IPDs = invasive pneumococcal disease, SCD = sickle cell disease, CSF = cerebrospinal fluid, HIV = human immunodeficiency virus.

Protein-based pneumococcal vaccines are purified protein vaccines (PPVs) that use select conserved proteins shared by all strains of pneumococcal bacteria regardless of their capsular glycans [20] - [22] . Most PPVs target surface proteins which anchor the bacteria to the human epithelial cells, providing wider protection not covered by PCVs, and to overcome the prevailing obstacles with serotype-dependent PCVs [20] [21] [23] [24] . Natural immunity to IPD is determined by production of antibodies against protein antigens when compared to capsular antigens [20] . PPVs such as pneumococcal histidine triad protein D (PhtD), pneumococcal choline-binding protein A (PcpA) and pneumolysin detoxified derivative (PlyD1) provide protection against AOM [20] [24] . Other widely studied PPVs include pneumococcal surface protein A (PspA), pneumococcal surface protein C (PspC), pneumococcal surface antigen A (PsaA), pneumococcal iron uptake A (PiuA) and pneumococcal iron acquisition A (PiaA) [21] .

The Pneumolysin (PLY) is a cholesterol-dependent cytolysin, which activates the classical pathway of the complement system, inflammation and causes direct cell toxicity [21] [23] . There are several PLY derivatives tested to provide protection against pneumococcal bacteria. PspA and PspC are choline-binding surface proteins on S. pneumoniae. It is widely expressed by capsular serotypes and is a critical virulence factor in pneumococci-host reactions. PspA-fusion protein and PspA-based trivalent vaccines have demonstrated efficacy against a wide range of pneumococcal strains in mice [21] [23] . Pht is a group of S. pneumoniae surface proteins with versatile immunogenicity with potential for non-serotype-dependent activity against pneumococcal infections, also involved in iron regulation [21] [24] . PhtD protects against pneumococcal sepsis [23] . PsaA is also surface lipoprotein with a strong immune response, that also reduces nasopharyngeal colonization. PiuA and PiaA are surface iron transport proteins that provide systemic protection against S. pneumoniae (i.e. in both serum and respiratory fluids) [21] . However, PPVs require adjuvants for lasting immunity, are largely variable in heterogenicity and need to be studied in depth [20] [21] [23] . Non-repeating sequences in protein antigens makes it difficult to mount a defensive antibody-antigen mediated immunity, especially against surface bacterial pathogens [23] .

There is demonstrable evidence of the role of Pneumococcal vaccines in reducing respiratory disease burdens and curbing exacerbations of chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD), cystic fibrosis and asthma. There is an established co-adjuvant relationship between S. Pneumoniae and respiratory viruses such as the influenza virus [25] . This pneumococcal-viral interaction, including bacterial host carriage, which alters host defenses, is also implicated in the pathogenicity of COVID-19. PCVs reduce pneumococcal colonization of the respiratory tract and thus reduce secondary viral infections, as well as the risk of coronavirus respiratory diseases, including COVID-19 [25] .

Reductions in disease burden: In preventing pneumococcal disease, different vaccine schedules have proven to reduce the disease incidence in children. This also translates to reduced use of antibiotics and lower treatment costs from an economic perspective. Studies have pointed PCV-7’s 50% - 60% reduction in disease burden due to the pneumococcal serotypes included in the vaccine [30] . In 2000, when the PCV-7 was introduced in the United States for children below 2yrs with a vaccine catch-up program for children up to 5 years old, this led to a decrease in the annual incidence of IPDs from about 16,000 - 18,000 cases between 1997-1997 to less than 5000 cases annually between 2002 and 2019. The number of healthcare visits for children with otitis media caused by S. pneumoniae was reduced by 50% between 1997 and 2019 [15] .

Changes in pneumococcal serotypes and impact on antibiotic resistance: The S. pneumoniae cell wall is composed of peptidoglycan and teichoic acid [31] . Teichoic acid has a significant component, the C-polysaccharide which is present in all wild strains of S. pneumoniae, and this is important in differentiating the serotypes. The serotypes can be grouped based on the antigenic component of their capsules [31] . These capsules are also important in developing antibiotic resistance. Many serotypes use capsular gene cassette transformation to enhance a change in capsule specificity and cause antibiotic resistance [31] . S. pneumoniae antibiotic resistance steadily increased between 1998-2021, thus posing a serious health threat [32] . Since pneumococcal vaccines target streptococcal serotypes, they protect against many antibiotic-resistant IPDs [32] [33] . Pneumococcal vaccines have been found in a study to reduce any type of antibiotic use, a number of people receiving antibiotics, the number of prescriptions, and the days of antibiotic use [33] . The serotypes 6A, 6B, 9V, 14, 19A, 19F, and 23F were known to cause the highest burden of antibiotic-resistant S. pneumoniae before 2000 however after the introduction of PCV7 in 2000 there was a decrease in infection rates by all these serotypes except 19A [32] . PCV13 which was introduced in 2010 contained the 19A serotype effectively reducing its disease burden [32] .

Effectiveness of vaccine strategies: The introduction of pneumococcal vaccines caused a significant reduction in pneumococcal disease burden, and helped establish herd immunity further reducing disease incidence. With the development of each new vaccine a stronger and wider disease coverage was received with each new vaccine. For example, PCV7 has led to a 50% - 60% reduction in disease burden for serotypes included in the vaccine, and PCV13 which hassled to a 90% decrease in invasive pneumococcal serotype infections since their introduction. Although the PPSV23 had a decreased efficacy towards providing immunity for children and infants due to the perseverance of serotypes, the evolution of PCV7 and PCV13 help counter those limitations. However, distribution and supply shortage has limited the availability of the pneumococcal vaccines to remote areas. Break in cold chain vaccine transport is also a challenge that the WHO is combating. Vaccine hesitancy and behavioural factors also reduces the response to vaccination and immunity.

In Canada, IPDs are prevalent in the very young and elderly (65 years+); the vaccine schedule has been updated to include the use of PCV 15 and 20, rather than the previously used PCV13 [34] . In children 2 months - less than 18 years, without medical or environmental IPD risk factors, routine immunization with PCV15 (Pneu-C-15) or PCV20 (Pneu-C-20) follows a 3-dose schedule (2, 4 and 12 months of age) or 4-dose schedule (2, 4 and 6 months, and at 12 - 15 months of age). All adults 65 years + should receive one dose of PCV20 regardless of previous status with PCV13 or PPSV23 and given at a minimum of one-year interval from the last PCV13 or PPSV23 dose in previously vaccinated seniors [34] . They can also be offered PCV15 followed by PPSV23 as an alternative, with an interval of 8 weeks between PCV15 as the first dose. Children at increased of IPD who have completed recommended PCV13 or PCV15 schedules and adults 18 - 64 years with IPD specific risk factors are offered one dose of PCV20 with minimum of one-year interval from the last PCV dose received. No additional doses of PCV20 or PPSV23 are required for children with completed vaccine series for age which included at least one dose of PCV20 [34] .

In the UK, infant PCV schedule was introduced since 2006 with PCV7, later replaced with PCV13 by 2010 [35] . The PCV13 immunization schedule is used and has achieved herd immunity [35] . The Joint Committee of Vaccination and Immunisation (JVCI) concluded that since the maximum effect of the PCV13 has been achieved in the UK reducing disease or asymptomatic carriage to the barest minimum, doses of PCV13 will be administered as 1 + 1 schedule, shifting from the previous 2 + 1 schedule, offered at 12 weeks and one year of age [35] . Children born on or after January 1, 2020, are offered a single dose of PCV13 at 12 weeks old, along with routine vaccinations, followed by PCV13 booster doses at their first birthday, in a 1 + 1 PCV13 schedule. Whereas infants born on or before December 31, 2019, continue to receive two doses of PCV13 at 8 and 16 weeks old, followed by a booster dose at their first birthday, in 2 + 1 schedule. Additional doses of PCV13 are recommended for immunosuppression, asplenia or severe splenic dysfunction like in the US. Other clinical risk groups follow the regular national schedule. This new schedule reduces how much vaccines are given during clinic visits and allows opportunity to introduce new future vaccines [35] .

Pediatric pneumococcal disease exacts a substantial burden on global health, much of which is vaccine preventable. Despite this considerable burden and the demonstrably high efficacy of PCVs, the overall level of PCV uptake remains concerningly low, especially compared with that of other childhood-recommended vaccines, such as tuberculosis and polio. A wide array of plausible expositions exists for this low uptake, including logistical challenges, psychosocial factors, and cost-effectiveness. Although decisions regarding PCV introduction and recommendation vary by country, an increasing number of both high- and low-income countries now incorporate PCV into their national immunization programs (NIPs). As of March 2019, 147 countries had introduced one or more PCVs into their NIPs (including 136 universal, five subnational, and three special risk programs), and 15 countries had announced plans to introduce a PCV [26] . These 147 countries include 60 low-income countries eligible for international assistance in procuring vaccines that introduced PCV after 2009 (the year in which funding from Gavi, the Vaccine Alliance, became available for PCVs) [36] . Figure 2 shows global PCV coverage by countries.

Reductions in the worldwide burden of childhood pneumococcal diseases reflect the widespread adoption of pneumococcal vaccines over the past two decades. Within the past 10 years, the total number of countries that have introduced PCVs (in at least one population and at least one region) has more than quadrupled. Despite these recent progress and relative growth in vaccine coverage, the

universal acceptance level of PCV is still subpar. The World Health Organization (WHO) estimates that global coverage of the third dose of PCV, while notably greater than in 2014, still only reached 48% of its target population in 2018 [37] . Table 4 below describes the percentage of the global population in the last 10 years who were vaccinated annually, and Figure 3 illustrates the trend in annual vaccination during the same period.

Many barriers and obstacles can impede PCV uptake. From a logistical standpoint, sustaining high coverage rates requires a dependable supply chain network, which has become increasingly challenging due to widening varieties of available vaccines, increasing supply costs, and tightening infrastructure standards. Many existing immunization and supply chain logistics (ISCL) systems are not keeping pace with the changing vaccine landscape, often resulting in stock shortages, inventory unpredictability, the potential administration of ineffective vaccines and avoidable wastage. The WHO estimates that in 2011, cold-chain failures in five countries resulted in the loss of 2.8 million vaccine doses [38] .

Even when existing ISCL systems are running smoothly and efficiently for the areas that they serve, accessibility often remains an especially important consideration for uptake in developing and rural areas. In underserviced areas, limitations such as travel opportunity costs, direct costs, and safety concerns may play a larger role in vaccination decisions. Children born to families living farther away from a road or clinic are at demonstrably greater risk of not being fully vaccinated, even where vaccines are reliably available and reimbursed [36] . Accessibility shortcomings and insufficient ISCL system funding both have far-reaching implications for vaccine coverage, uptake, and—in cases of noncompletion—efficacy [38] .

Behavioral and psychosocial considerations are also key determinants of vaccination uptake [36] . Vaccine hesitancy is one leading impediment to sustaining high coverage rates and is common worldwide: more than 90% of countries reported some level of vaccine hesitancy [39] . The top three reasons cited for vaccine hesitancy globally in 2016 were 1) risk-benefit concerns (such as vaccine safety concerns, 23% of responses); 2) lack of knowledge and awareness of vaccination and its importance (10%); and 3) religion, culture, gender, and socioeconomic issues regarding vaccines (12%) [39] . The spread of misinformation through anti-vaccination lobbies and the media exerts a powerful influence on parents’ vaccination decisions and perceptions of vaccine safety. Another basis of low pediatric PCV uptake is affordability. PCVs are more expensive than earlier generations of vaccines, and their prices have been rising in the United States and globally [40] [41] .

One other plausible major and systemic cause of low uptake is economists’ and policymakers’ tendency to undervalue vaccination in general, particularly PCVs, by adopting a narrow health sector perspective when performing economic evaluations of vaccines. The conventional health sector perspective focuses on two benefit categories of vaccination: healthcare cost savings (stemming from reductions in visits to healthcare professionals, inpatient stays, and prescription drugs) and health gains (the value of reduced morbidity, mortality, and suffering from pneumococcal diseases). These two benefit measures alone are inadequate to establish a panoramic assessment of the value of PCVs, as they do not capture a much broader set of socioeconomic benefits to society [37] .

Despite the increase in vaccination rates with the pneumococcal vaccines, there are still missed opportunities for vaccination, such as at the time of hospital discharge or clinic visits, [1] as well as vaccine hesitancy. Other avenues to offer pneumococcal vaccination include nursing homes and long-term care facilities. Early identification through screening and vaccination of at-risk groups especially in hospitalized populations would remarkably reduce morbidity and mortality from pneumococcal diseases [1] . The lack of a vaccine that can protect against all pneumococcal serotypes as well as the spread of resistant serotypes pose significant challenges for both pneumococcal vaccines and antibiotic-resistant pneumococcus [37] . The CDC recommends that expanding vaccine use can prevent future infections, slow, and even reverse emerging antibiotic resistance [37] . According to Dunne et al., the knowledge gap between host responses, viral and pneumococcal respiratory infections, and the role of PCVs need to be explored further [25] . Cai et all surmised that newer vaccines that target all strains, can reduce disease burden as well as asymptomatic carriage [42] . A non-dependent-serotype protein vaccine is also an advantageous and more affordable pneumococcal vaccine option for children in third world countries, providing extensive coverage against geographical serotypes against IPDs and other pneumococcal infections, thus curbing the global impact of pneumococcal diseases [23] [24] .

Active surveillance will continue to identify populations with vaccine hesitancy, low vaccine uptake, and poor vaccine education as well as growing antibiotic resistance. Constant public reminders such as vaccine education and advocacy on the unparalleled importance of vaccination and herd immunity, will promote active vaccine acceptance and uptake and reduce cost association with antibiotic resistance and treatment of pneumococcal infection.

Prioritization of vaccination scheme: this involves initiatives such as pharmacist-led distribution programs, standing orders for nurses to administer vaccines and appropriate protocols for distribution, improved protocols for eligibility (e.g. notification within electronic medical record when accessing a patient’s chart, standardized checklist guidelines), and routine vaccination guidelines on a national level. A study by Patel et al. showed that pharmacy-led teams in the United States increased national immunizations by an estimated 3.5 million doses per year [43] [44] .

Removing practical barriers to immunization such as access: Limited access to vaccination is one of the leading causes to reduced coverage (e.g. limited opening hours, distance to health centers, inconvenient booking system). Improving on the booking system such that individuals can book and receive vaccination same day would increase the rate of vaccination. In addition, the creation of mobile vaccination units will reduce the distance between individuals and vaccination sites [45] .

Use of immunization information system: Immunization information systems (IIS) are confidential, computerized, population-based systems that collect and consolidate vaccination data from vaccination providers and provide important tools for designing and sustaining effective immunization strategies at the provider and immunization program levels. These tools include clinical decision support, vaccination coverage reports, interoperability with electronic health record systems, vaccine inventory management, and the ability to generate reminder and recall messages. Patient recall and reminder systems such as sending text messages or phone calls to individuals to remind them of their upcoming vaccination appointment or pending vaccination booking have shown to be an effective way to increase coverage [46] [47] .