The first known pneumococcal vaccines in the United States date back to 1909 in the form of heat-treated whole-cell vaccines. These early vaccines remained available until the mid-XNUMXs, and many of these products contained additional vaccines aimed at preventing diseases caused by Haemophilus influenzae, Staphylococcus aureus, Klebsiella, Neisseria catarrhalis, and others.⁽¹⁾
The first pneumococcal vaccine trials began in South Africa in 1911 and involved miners who were given a whole-cell vaccine composed of known circulating strains of pneumococcus. The results of this first study were improperly recorded, and as a result a second trial with a vaccine of similar formulation was started in the summer of 1912. This second vaccine reportedly offered some protection from pneumonia, but that protection only lasted about 2 months. Also, while the vaccination appeared to reduce the pneumonia rate slightly, it had no impact on the pneumonia death rate.

A third study, involving the use of a similar pneumococcal vaccine, was reported to reduce pneumonia rates by 25-50% and mortality rates by 40-50%.⁽²⁾ Sir Almroth Knight, the principal investigator involved in the first three clinical trials, however, paid no attention to the strains of pneumonia used in the vaccines, making it difficult to determine the overall effectiveness of pneumococcal vaccination.⁽³⁾ Sir F. Spencer Lister, a protégé of Sir Almroth Knight, expanded on Knight's earlier work by developing a system for identifying and typing different strains of pneumococcus. Lister noted the presence of unique strains of pneumococcus not found in North America and Europe.
In 1914, Lister developed the first whole-cell pneumococcal vaccine containing three specific strains of S. pneumoniae, known today as serotypes 1, 2, and 5.⁽⁴⁾ Lister's vaccine studies involved giving 3 doses of vaccine a week apart to miners working in 3 different South African mines. In all three mines there was a decrease in pneumococcal morbidity and mortality in the six to twelve months of observation following vaccination.⁽⁵⁾
In 1918, Lister expanded his vaccine by adding five more strains of pneumococcus and planned to give this vaccine to all South African miners. However, in the mid-twenties, his vaccine proved ineffective. In the early 30s, pneumonia caused by strains 1, 2, 5 and 7, four of his vaccine's target strains, remained low; however, rates of pneumonia caused by strain 3, a strain also found in its vaccine, were noted to be three times higher among those who received the vaccine.⁽⁶⁾

During World War I, pneumococcal vaccination campaigns were started at 2 US military bases, and troops were vaccinated with a pneumococcal vaccine containing strains 1, 2, and 3. Vaccination was found to reduce the rates of pneumonia caused by from specific vaccine strains, but vaccine recipients were only studied over a period of 2-3 months, and the long-term efficacy of the vaccine was never determined.^(7-8)

Pneumococcal vaccines were also administered in a variety of settings during the 1918 flu pandemic, including at military bases, with mixed efficacy. Vaccines given during this period also included strains of other bacteria, such as B. influenza, Staphylococcus aureus or haemolytic streptococci.⁽⁹⁾

The capsular polysaccharides of pneumococcus were discovered in 1916-1917, but it took until 1927 for researchers to figure out that the polysaccharides could induce an immune response. The first pneumococcal polysaccharide vaccine contained strain 1 and strain 2. The vaccine was administered to approximately 120.000 Civilian Conservation Corp (CCC) men in the 30s in several clinical trials. The efficacy of the vaccine was studied for only a few months and no long-term studies were ever completed.^(10-11)

In 1937, a polysaccharide vaccine containing pneumococcal strain (serotype) 1 was used during a pneumonia epidemic in an adult psychiatric hospital. This study reported that the vaccine significantly reduced rates of pneumonia.^(12-13)

Both military and civilian clinical trials of pneumococcal polysaccharide vaccines have yielded favorable results,^(14-15) and in 1947 the first licenses for the pneumococcal polysaccharide vaccine were granted to E. R. Squibb & Sons.⁽¹⁶⁾ The adult Squibb vaccine contained serotypes 1, 2, 3, 5, 7, and 8, while the pediatric vaccine contained serotypes 1, 4, 6, 14, 18, and 19.⁽¹⁷⁾ The use of these vaccines was short-lived, as doctors preferred to use newly discovered antibiotics to treat pneumonia. Production of pneumococcal polysaccharide vaccines ended in 1951 and 1954.

Eli Lilly & Co was awarded a contract by the NIH for research and development of an effective pneumococcal polysaccharide vaccine. In 1972, testing of Eli Lilly's pneumococcal vaccine began in South Africa;(20) however, by 1975, Eli Lilly had discontinued research and development activities after experiencing several problems with the vaccine.^(21-22)
Meanwhile, Merck Sharp and Dohme, building on the knowledge and experience gained from research and development of a meningococcal polysaccharide vaccine for the US Army in the late 60s, had already begun development of a polysaccharide vaccine pneumococcal in 1970. Merck also chose to complete clinical trials of the pneumococcal vaccine in South Africa and reported that its 6- and 12-step vaccines reduced rates of pneumococcal pneumonia disease by 76 and 92 percent, respectively.⁽²³⁾

In 1976, Merck applied for a license to manufacture and market a 14-valent capsular polysaccharide vaccine, PNEUMOVAX, which was approved by the FDA on November 21, 1977.⁽²⁴⁾ In January 1978, the CDC's Advisory Committee on Immunization Practices (ACIP) recommended that the new pneumococcal vaccine be given to all children and adults age 2 and older with chronic health conditions, including sickle cell disease, splenic dysfunction, diabetes mellitus and chronic kidney, lung, liver and renal diseases. The vaccine has also been approved for use during a pneumococcal outbreak involving a closed population, such as a nursing home or similar institution.⁽²⁵⁾

Lederle, another established vaccine company, had also begun research and development of a pneumococcal polysaccharide vaccine in the 70s, and in August 1979, PNU-IMUNE, its 14-valent pneumococcal vaccine, received the FDA approval.⁽²⁶⁾

In the early 80s, pneumococcal experts recognized the need to expand the number of pneumococcal strains contained in the polysaccharide vaccine to improve coverage on a global scale. The World Health Organization (WHO), together with the governments of several countries, reported that a 23-valent pneumococcal vaccine would provide better protection against pneumococcal disease worldwide. In 1983, Merck and Lederle introduced pneumococcal polysaccharide vaccines (PPV23) containing 23 pneumococcal strains that were believed to cause approximately 87% of all cases of bacterial pneumonia in the United States. The PPV23 vaccines have been reformulated to contain 25mcg of each specific antigen, a decrease from the 50mcg per antigen found in the 14-valent vaccine, in an effort to better balance safety and immune response.⁽²⁷⁾
The CDC's Advisory Committee on Immunization Practices (ACIP) voted in 1984 to recommend that all adults 65 years and older receive one dose of PPV23 vaccine. This recommendation was made despite the knowledge that 2 separate studies had found the vaccine to be ineffective in reducing pneumococcal infections and deaths.⁽²⁸⁾ ACIP also continued to recommend that all adults and children aged 2 years and older with chronic conditions or immunosuppression receive one dose of the vaccine.⁽²⁹⁾

In 1997, the recommendations for PPV23 were updated to include special populations such as individuals living in nursing homes and other long-term care facilities and for use in Alaska Native and some American Indian populations.⁽³⁰⁾

Because pneumococcal polysaccharide vaccines have proven ineffective in children younger than 2 years of age, vaccine development continued.⁽³¹⁾ Pneumococcal-related deaths were infrequent among children except in cases of immunosuppression, meningitis, or severe bacteremia following removal of the spleen, but children 2 years of age and younger and adults 65 years of age and older at age XNUMX are still considered by health officials to be at higher risk for pneumococcal infections.⁽³²⁾

Development of a method to bind a polysaccharide with a carrier protein to enhance the immune response began in 1980, and in 1987 the Hib conjugate vaccine was the first vaccine using polysaccharide-protein conjugation technology to receive FDA approval .⁽³³⁾

Wyeth Lederle was the first vaccine manufacturer to develop a pneumococcal conjugate vaccine. In pre-licensing clinical trials, Prevnar 7 (PCV7) was tested against an investigational meningitis C vaccine,⁽³⁴⁾ which seriously compromised the scientific validity of the experiment. The vaccine, however, still received FDA approval in February 2000.⁽³⁵⁾

The 7-valent pneumococcal conjugate vaccine contained Streptococcus pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F individually conjugated to the diphtheria CRM197 protein and was approved for use in infants and children at 2, 4, 6 and 12-15 months of age for the prevention of invasive disease caused by Streptococcus pneumoniae by the strains present in the vaccine.⁽³⁶⁾

On June 21, 2000, the CDC's Advisory Committee on Immunization Practices (ACIP) voted to recommend use of the PCV7 vaccine in all children 23 months of age and younger, as well as in children ages 24 to 59 months considered at high risk for severe pneumococcal infection.⁽³⁷⁾ Highly successful promotion by Wyeth Lederle, the CDC, and the American Academy of Pediatrics (AAP) made Prevnar (PCV7) the best-selling new drug product of 2000, with sales of $461 million.⁽³⁸⁾

In October 2002, the FDA approved PCV7 for the prevention of middle ear infections (otitis media), despite clinical trials finding that the vaccine was only 7% effective against all types of acute otitis media.^(39-40)

Following the introduction of PCV7 on a global scale, scientists began reporting that although the vaccine appeared effective in reducing nasopharyngeal carriage of S. pneumoniae strains present in the vaccine, this reduction had led to a significant increase in non-vaccine type,⁽⁴¹⁾ in particular strain 19A, a highly virulent and antibiotic-resistant serotype.^(42-43) In Spain, there has been an increase in invasive pneumococcal disease following the introduction of PCV7, with the appearance of several non-vaccine strains.^(44-45-46)

Vaccine manufacturers have responded to the emergence of more antibiotic-resistant S. pneumoniae strains by introducing new pneumococcal vaccines containing additional strains. In March 2009, Synflorix (PCV10), a 10-valent pneumococcal conjugate vaccine, containing three additional strains not present in PCV7 (1, 5, and 7F) received approval for use in Europe.⁽⁴⁷⁾ One year later, in February 2010, Wyeth pharmaceuticals received approval for Prevnar 13 (PCV13), a 13-valent pneumococcal conjugate vaccine, which added 6 additional strains (1, 3, 5, 6A, 7F, and 19A ) to the original Prevnar vaccine (PCV).⁽⁴⁸⁾

Recommendations for the use of PCV13 were promptly issued by the CDC's Advisory Committee on Immunization Practices (ACIP), which essentially recommended using PCV13 in place of PCV7. Prior to FDA approval, PCV13 was studied for safety in fewer than 4.800 healthy infants and children, and the vaccine was compared with infants and children receiving PCV7, alone or in combination with other vaccines .⁽⁴⁹⁾

ACIP also recommended PCV13 for previously unvaccinated children and adolescents ages 6 to 18 who are considered at high risk for pneumococcal disease due to immunosuppressive conditions, including sickle cell disease, asplenia, HIV, the presence of a cochlear implant or cerebrospinal fluid leak.^(50-51) At the time of this recommendation in December 2010, the FDA had not approved the vaccine for use in children older than 59 months and had not expanded the use of the PCV13 vaccine to children and adolescents aged ages 6 to 17 until January 2013.⁽⁵²⁾

In December 2011, the FDA approved expanded use of PCV13 under an "accelerated approval" process to include adults aged 50 and older.⁽⁵³⁾ The "accelerated approval" process allows products intended to treat a serious condition or fill an unmet need to receive faster approval from the FDA based on laboratory testing or other measurements believed to predict clinical benefit .⁽⁵⁴⁾ In this case, a comparison was made between the antibody responses of subjects who received PCV13 or Merck's 23-valent polysaccharide vaccine (PPSV23). PCV 13 was found to have a similar or greater antibody response than PPSV23, and the FDA allowed this laboratory result to meet the requirement to receive accelerated approval, despite knowing that the level of vaccine-induced antibodies needed to protect an individual from a particular strain of pneumococcal infection is unknown.^(55-56)

Although ACIP declined to routinely recommend PCV13 for adults over age 50 following FDA approval to expand its use,⁽⁵⁷⁾ the committee voted to recommend the vaccine for use in immunocompromised adults 19 years and older in June 2012.⁽⁵⁸⁾ The FDA, however, did not approve PCV13 for use in adults ages 19 to 49 until July 11, 2016.⁽⁵⁹⁾

In 2014, ACIP updated its recommendations for the use of PCV13, recommending that the vaccine be administered to all older adults 65 years and older in addition to the previously recommended PPSV23 vaccine;⁽⁶⁰⁾ however, in October 2018, ACIP reported that this recommendation did not reduce pneumonia rates among people 65 and older.⁽⁶¹⁾

Since the introduction of PCV13, pneumococcal strains not covered by the vaccine have continued to emerge. US researchers have noted that while invasive pneumococcal disease has declined since the introduction of pneumococcal conjugate vaccines, S. pneumoniae strains have adapted and antibiotic-resistant non-vaccine strains have emerged.^(62-63) These nonvaccine strains include strains 33F, 22F, 12, 15B, 15C, and 23A.⁽⁶⁴⁾

Korea too,⁽⁶⁵⁾ Taiwan,⁽⁶⁶⁾ and several Western European countries,⁽⁶⁷⁾ have reported an increase in pneumococcal strains not covered by PCV13, and scientists continue to recommend monitoring of pneumococcal strains and further vaccine development in response to the continued emergence of non-vaccine-type strains.^{(68-69-70-71-72)}