Pneumococcal Vaccination during COVID-19: Comparison
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The emergence of new viral infections has increased over the decades. The novel virus is one such pathogen liable for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, popularly known as coronavirus disease 2019 (COVID-19). Most fatalities during the past century’s influenza pandemics have cooperated with bacterial co/secondary infections. Unfortunately, many reports have claimed that bacterial co-infection is also predominant in COVID-19 patients (COVID-19 associated co/secondary infection prevalence is up to 45.0%). In the COVID-19 pandemic, Streptococcus pneumoniae is the most common coinfecting pathogen. Half of the COVID-19 mortality cases showed co-infection, and pneumonia-related COVID-19 mortality in patients >65 years was 23%. The weakening of immune function caused by COVID-19 remains a high-risk factor for pneumococcal disease. Pneumococcal disease and COVID-19 also have similar risk factors. For example, underlying medical conditions on COVID-19 and pneumococcal diseases increase the risk for severe illness at any age; COVID-19 is now considered a primary risk factor for pneumococcal pneumonia and invasive pneumococcal disease. Thus, pneumococcal vaccination during the COVID-19 pandemic has become more critical than ever. 

  • COVID-19
  • SARS-CoV-2
  • Streptococcus pneumoniae
  • co/secondary infections
  • superinfections
  • pneumococcal vaccination

1. Combined Infection with SARS-CoV-2 and S. pneumoniae

A common complication of respiratory viral disease is bacterial coinfection or secondary bacterial infection, which occurs during or after an infectious disease caused by another pathogenic virus [1]. These infections can worsen clinical outcomes and disease severity, consequently increasing morbidity and mortality [2].
Coinfection has been reported in patients with SARS and MERS [3][4], and similarly, bacterial coinfections have also been known as prevalent complications in COVID-19 patients [5]. Reports show that SARS-CoV-2 may strengthen bacterial colonization and attachment to the host tissue, and the concurrent infections may result in irreversible tissue damage and enhanced pathophysiology [4]. Furthermore, several studies have revealed that the prevalence of COVID-19-associated co/secondary infection is as high as 45.0% [3] and that half of mortalities occurred due to secondary bacterial infections [6]. Additionally, COVID-19 patients with a bacterial coinfection were 5.82 times more likely to die than COVID-19 patients who did not have a coinfection [7].
Another crucial issue occurs when superinfections accompany COVID-19. One study reported that 24% of COVID-19 patients had superinfections, were described to be more severely ill, and had a higher risk of mortality. It appeared to be mainly due to the resistance of the superinfection to previously used antibiotics. Although the actual incidence of bacterial superinfections in COVID-19 is unknown so far, superinfections are expected to pose a significant challenge in the management of COVID-19 patients [8].
Key findings from recent studies have consistently shown a positive association between co/secondary bacterial infection or superinfection and an increased risk of mortality among COVID-19 patients [9][10].

2. Recommendations for Two Vaccine-Preventable Diseases (VPDs)

2.1. Impact of Pneumococcal Vaccines in COVID-19

Vaccination is the most beneficial health policy for improving public health and reducing the impact of infectious disease. In particular, the current public health burden of S. pneumoniae infection has been reduced by vaccine tools demonstrated by the results of administering pneumococcal polysaccharide vaccine (PPSV23) and pneumococcal conjugate vaccine (PCV13) in adults [11]. PPSV23 and PCV13 have different immunological mechanisms to activate antipneumonia immune responses. PPSV23, composed of purified polysaccharides, triggers a T-cell-independent activation to activate B cells [12]. However, the memory B cells generated during the response of T-cell independent PPSV23 are short-lived and create a week antibody production upon re-exposure to the antigen [13]. Thus, vaccines containing capsular polysaccharides alone, such as PPSV23, have low immunogenicity in immunocompromised patients [14].
A nontoxic CRM197 carrier protein conjugated in PCV13 triggers a T-cell-dependent response. In contrast to PPSV23, the protein-polysaccharide conjugate (PCV13) binds to B cell receptors. The subsequent signaling promotes the generation and proliferation of long-lived memory B cells that secrete isotype-switched and affinity-maturated antibodies [15]. A randomized, double-blind, placebo-controlled trial (the Community-Acquired Pneumonia Immunization Trial in Adults) in the Netherlands involving 84,496 adults aged ≥ 65 years from 2008 to 2013 reported a 45.5% efficacy for PCV13 against all vaccine-type pneumococcal CAP, a 45% efficacy against vaccine-type nonbacteremic pneumococcal CAP, and a 75% efficacy against vaccine-type IPD [16]. The CDC recommends PCV13 for all children < 2 years of age and children aged ≥ 2 years with certain medical conditions. Adults aged ≥ 65 years can select whether to get PCV13 or PPSV23 vaccinations, whereas individuals between 2 and 64 years of age are only eligible if they have certain medical conditions [17]. Currently, many researchers are looking at the possibility of preventive methods that can lower COVID-19 mortality and morbidity. Despite the unknown interaction of pneumococcal disease and COVID-19 [18], the WHO has announced that vaccines against pneumonia, including pneumococcal vaccines and the Haemophilus influenza type B (Hib) vaccine, do not protect against any types of pneumonia caused by coronaviruses, including COVID-19 [19][20].
However, a recent Mayo Clinic study reported powerful associations between pneumococcal vaccination and COVID-19 immunity [21][22], reporting that older PCV13-vaccinated adults acquired certain pneumococcal strains and experienced a 35% lower risk of COVID-19 infection than the unvaccinated adults. In contrast, an alternative pneumococcal vaccine (PPSV23) prevented severe pneumococcal disease but did not generate the same immunity to block bacterial acquisitions [23]. Another randomized controlled trial with children and adults [24][25][26][27] found PCVs to confer 23 to 49% protection against pneumonia-associated respiratory viruses, including human coronavirus [25][26], supporting the etiologic involvement of pneumococci in virus-associated respiratory disease. Lewnard et al. [23] estimated adjusted hazard ratios (aHRs) for the association of COVID-19 with PCV13 from the data accumulated among 531,033 adults and provided convincing results showing that prior pneumococcal vaccination reduced the clinical outcomes of COVID-19. Another study analyzed data from the 51 nations and found a strong negative correlation between pneumococcal vaccination and COVID-19 case and death rates [28].
Direct prevention may be difficult despite these findings since the pneumococcal vaccine is not a “dedicated” vaccine for COVID-19. Therefore, the question arises whether bacterial vaccines can prevent the transmission of the virus, given that the pneumococcal vaccine has been reported to avoid a substantial burden of targeted diseases and mortality among adults at risk [29]. The CDC Advisory Committee on Immunization Practices recommends the use of the 13-valent pneumococcal conjugate vaccine (PCV13) and 23-valent pneumococcal polysaccharide vaccine (PPSV23) for adults aged ≥ 19 years (Table 1) [30].
Table 1. Recommendations for the 13-valent pneumococcal conjugate vaccine (PCV13) and 23-valent pneumococcal polysaccharide vaccine (PPSV23) among adults aged ≥ 19 years.
Medical Indication Group Specific Underlying Medical Condition PCV13 for Persons

Aged ≥ 19 Years		 PPSV23 * for Persons

Aged 19–64 Years		 PCV13 for Persons

Aged ≥ 65 Years		 PPSV23 for Persons

Aged ≥ 65 Years
None None of the below No recommendation No recommendation Based on shared clinical decision-making † 1 dose; if PCV13 has been administered, then administer PPSV23 ≥ 1 year after PCV13
Immunocompetent

persons		 Alcoholism No recommendation 1 dose Based on shared clinical decision-making † 1 dose; if PCV13 has been administered, then administer PPSV23 ≥ 1 year after PCV13 and ≥ 5 years after any PPSV23 at age < 65 years
Chronic heart disease §
Chronic liver disease
Chronic lung disease
Cigarette smoking
Diabetes mellitus
Cochlear implant 1 dose 1 dose ≥ 8 weeks after PCV13 1 dose if no previous PCV13 vaccination 1 dose ≥ 8 weeks after PCV13 and ≥ 5 years after any PPSV23 at < 65 years
CSF leak
Immunocompromised

persons		 Congenital or acquired asplenia 1 dose 2 doses, 1st dose ≥ 8 weeks after PCV13 and 2nd dose ≥ 5 years after first PPSV23 dose 1 dose if no previous PCV13 vaccination dose ≥ 8 weeks after PCV13 and ≥ 5 years after any PPSV23 at < 65 years
Sickle cell disease/other hemoglobinopathies
Chronic renal failure
Congenital or acquired immunodeficiencies **
Generalized malignancy
HIV infection
Hodgkin disease
Iatrogenic immunosuppression ††
Leukemia
Lymphoma
Multiple myeloma
Nephrotic syndrome
Solid-organ transplant
ACIP = Advisory Committee on Immunization Practices; CSF = cerebrospinal fluid; HIV = human immunodeficiency virus. * Refers only to adults aged 19–64 years. All adults aged ≥ 65 years should receive 1 dose of PPSV23 ≥ 5 years after any previous PPSV23 dose regardless of the previous history of vaccination with pneumococcal vaccine. No additional doses of PPSV23 should be administered following the dose administered at age ≥ 65 years. † Recommendations that changed in 2019. § Includes congestive heart failure and cardiomyopathies. Includes chronic obstructive pulmonary disease, emphysema, and asthma. ** Includes B- (humoral) or T-lymphocyte deficiency, complement deficiencies (particularly C1, C2, C3, and C4 deficiencies), and phagocytic disorders (excluding chronic granulomatous disease). †† Diseases requiring treatment with immunosuppressive drugs including long-term systemic corticosteroids and radiation therapy.

 

 

 

 

2.2. Recommendations of Pneumococcal Vaccine for Reducing the Risk of COVID-19

In most high-income countries, such as the United States, United Kingdom, Sweden, Germany, France, Norway, and Italy, the pneumococcal vaccination rate for adults is high because vaccination is recommended and free for those over 65 years of age. However, vaccination is just advised for older adults in several countries, such as Switzerland, South Korea, and Australia. The rate is rare even in low- and middle-income countries [31]. Therefore, there are several recommendations that clinics and patients can implement to reduce the risk of COVID-19. First and foremost, patients should be immunized to reduce the risk of preventable coinfections with other viruses. Specifically, they should receive vaccines against S. pneumoniae (PCV13 and PPSV23) [32]. Such vaccinations could stimulate an immune response in older adults; although the data are not fully supportive of this hypothesis, pneumococcal vaccinations could reduce the risk and potentially severe infections, including COVID-19 [33][34][35]. Thindwa et al. [29] estimated COVID-19 mortality associated with pneumococcal coinfection and reported that PPSV23 in older adults could reduce potentially pneumococcal-attributable COVID-19 morbidity and mortality.
Data analysis of the EPI COVID-19 survey indicates that pneumococcal vaccinations and/or coadministration of influenza vaccines can reduce the risk of being infected with SARS-CoV-2, although further supporting evidence is still required to confirm this possibility. Considering that multiple respiratory coinfections can frequently lead to fatal respiratory failure, especially in older age, some research claims collaborative public health programs to enhance antipneumococcal and anti-influenza vaccination campaigns. Therefore, special attention should be paid to the individuals in the most vulnerable categories of risk factors to reduce severe COVID-19 prognosis.
The Pan American Health Organization guides the conduct of immunization programs in the context of the COVID-19 pandemic, recognizing that healthcare systems face a rapid increase in demands. If healthcare systems become overwhelmed, both mortality and morbidity from preventable and treatable conditions, such as VPDs, increase dramatically [36]. Any disruption of health services, even for a short time, will increase the number of individuals susceptible to infections, increasing the likelihood of VPD outbreaks. Such outbreaks may result in health crises and an increased burden on health systems, which are already strained with COVID-19 response operations. Since immunization is an essential component of health services, routine immunization programs should be maintained as long as COVID-19 response measures allow. Furthermore, one of the guiding principles for immunization programs during the COVID-19 pandemic must include prioritizing pneumococcal and seasonal influenza vaccines for vulnerable population groups [37].
It was especially timely guidance since influenza and pneumococcal vaccines were easily accessible when public health officials were challenged with a lack of effective COVID-19 vaccines during the 2020 autumn–winter season [38][39]. Spain [40] has also indicated that it is essential for patients with CKD, similar to patients with CVD, to remain up to date with their vaccinations, including the pneumococcal vaccine, given the increased risk of secondary bacterial infection with COVID-19. Moreover, Canada’s Ontario Ministry of Health [41] said the ongoing pneumococcal vaccination for the underlying conditions mentioned by the CDC should be prioritized.
Influenza and pneumococcal vaccines continue to be recommended for immunosuppressed individuals by the American Red Cross, New York City Health Department, European AIDS Clinical Society [42], and Australian Government Department regardless of the threat of COVID-19.

3. Conclusions

The new viral infection caused by SARS-CoV-2, popularly known as COVID-19, has spread worldwide, becoming the most dangerous pandemic threatening the global health system over the decades. We found that most fatalities during the past century’s influenza pandemics were associated with bacterial co/secondary infections. Similarly, reports have stated that bacterial coinfection is predominant in COVID-19 patients, with a co/secondary infection prevalence of up to 45.0%. This challenge needs close attention to the effect of concurrent infections, including co/secondary bacterial infections and superinfections, on the morbidity and mortality of COVID-19 patients. Based on previous studies, the predominant coinfection during the influenza pandemics since the late 1800s was by S. pneumoniae. During the COVID-19 pandemic, S. pneumoniae remains the most common coinfecting bacteria (59.5% coinfection rate of S. pneumoniae in coinfection cases).
Studies have shown that bacterial coinfection decreases immune function and increases the mortality of COVID-19 patients, with a 7.8-fold higher mortality in coinfected patients than in patients with only pneumonia. Half of the recorded COVID-19 mortalities were coinfected cases, and COVID-19 mortality due to pneumonia in patients > 65 years of age accounted for 23% of recorded mortalities because the weakening of immune function caused by COVID-19 remains a high-risk factor for pneumococcal disease. A detailed investigation of the impact of risk factors and underlying medical conditions on COVID-19 and pneumococcal diseases, such as old age, cancer, diabetes mellitus, asthma, smoking, and chronic diseases related to the heart, kidneys, and liver, revealed that pneumococcal disease and COVID-19 have similar risk factors.
Underlying medical conditions of patients of any age with S. pneumoniae increase the risk of severe illness; COVID-19 is now considered a primary risk factor for pneumococcal pneumonia and invasive pneumococcal disease. Given all these findings, pneumococcal vaccination during the COVID-19 pandemic is more critical than ever. To that end, we have presented positive studies of pneumococcal vaccination in patients with COVID-19 and underlying medical conditions in this review. Although the WHO has announced that bacterial vaccination does not protect against COVID-19 pneumonia, we have shown the correlation effect between pneumococcal disease and COVID-19 in preventing increased morbidities and mortalities by co/secondary infections and superinfections.
To strengthen the global health system in the campaign against COVID-19, we have presented why pneumococcal vaccination has a significant role in the current pandemic setting. This review supports the recommendation for pneumococcal disease vaccination and proffers the consequent relief from the COVID-19 pandemic.

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