What is the history of Pneumococcal vaccine use in America?

The first pneumococcal vaccine trials began in South Africa in 1911 and involved miners who were administered a whole-cell vaccine consisting of the known circulating strains of pneumococcal. The results of this first study were improperly recorded and as a result, a second trial of a similarly formulated vaccine was initiated in the summer of 1912. This second vaccine was reported to offer some protection from pneumonia but this protection lasted only about two months. Further, while vaccination appeared to slightly reduce pneumonia rate, it had no impact on pneumonia death rates.

A third trial which involved a similar pneumococcal vaccine was reported by investigators to decrease pneumonia rates by 25 to 50 percent and death rates by 40 to 50 percent.  Sir Almroth Knight, the primary researcher involved in the first three clinical trials, however, didn’t document the strains of pneumonia used within the vaccines, making the overall effectiveness of pneumococcal vaccination difficult to determine. 

Sir F. Spencer Lister, a protégé of Sir Almroth Knight, expanded on Knight’s earlier work by developing a system to identify and type different strains of pneumococcal. Lister noted the presence of unique pneumococcal strains not found in North America and Europe.

In 1914, Lister developed the first whole-cell pneumococcal vaccine containing three specific strains of S. pneumoniae, now known as serotypes 1, 2, and 5.  Lister’s vaccine trials involved the administration of three vaccine doses given one week apart to miners working at three different South African mines. All three mines experienced a decrease in pneumococcal morbidity and mortality in the six to twelve-month period of observation post-vaccination. 

By 1918, Lister expanded on his vaccine by adding five additional pneumococcal strains and planned to administer this vaccine to all South African miners. However, by the mid- 1920s, his vaccine was found to be ineffective. By the early 1930s, pneumonia caused by strains 1, 2, 5, and 7, four of the strains targeted by his vaccine, remained low; however, pneumonia rates from strain 3, a strain also found in his vaccine, were noted to be three times higher among those who received the vaccine.  

During the First World War, two U.S. military bases began pneumococcal vaccination campaigns 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 the strains specific to the vaccine but vaccine recipients were studied for a period of only two to three months and the long-term effectiveness of the vaccine was never determined.   

Pneumococcal vaccines were also administered in several settings during the 1918 flu pandemic, including military bases, with mixed effectiveness. Vaccines administered during this period also included strains of additional bacteria, such as B. influenza, Staphylococcus aureus, or hemolytic streptococci. 

Pneumococcal capsular polysaccharides were discovered in 1916-1917, but it took researchers until 1927 to realize that the polysaccharides could induce an immune response. The first pneumococcal polysaccharide vaccine contained pneumococcal strain 1 and strain 2, and the vaccine was administered to nearly 120,000 Civilian Conservation Corp (CCC) men in the 1930s as part of several clinical trial studies. The vaccine’s effectiveness was studied for only a few months and no long-term studies were ever completed.   

In 1937, a polysaccharide vaccine containing pneumococcal strain (serotype) 1 was used during a pneumonia outbreak at an adult psychiatric hospital. This trial reported that the vaccine significantly decreased pneumonia rates.   

Both military and civilian clinical trials of polysaccharide pneumococcal vaccines reported favorable results,    and in 1947, the first pneumococcal polysaccharide vaccine licenses were granted to E.R. Squibb & Sons.  Squibb’s adult vaccine contained serotypes 1, 2, 3, 5, 7 and 8 while its pediatric vaccine contained serotypes 1, 4, 6, 14, 18 and 19.  

Use of these vaccines was short-lived as doctors preferred to use newly discovered antibiotics to treat pneumonia. Production of polysaccharide pneumococcal vaccines ended in 1951 and in 1954, Squibb withdrew its vaccine license due to the lack of demand for the product.   

Pneumococcal vaccine development resumed again in 1968, this time at the insistence of National Institutes of Health (NIH) scientist Dr. Robert Austrian. Austrian had witnessed numerous antibiotic treatment failures in the clinical setting and believed pneumococcal disease rates to be much higher than reported due to a significant decrease in the use of testing to confirm a diagnosis.

Eli Lilly & Co was granted a contract by the NIH to research and develop an effective pneumococcal polysaccharide vaccine. In 1972, vaccine trials of Eli Lilly’s pneumococcal vaccine began in South Africa;  however, by 1975, Eli Lilly had terminated its research and development after several issues with the vaccine occurred.   

Meanwhile, Merck, Sharp, and Dohme, with knowledge and experience related to the research and development of a meningococcal polysaccharide vaccine for the United States Army in the late 1960s, had already started on a pneumococcal polysaccharide vaccine development by 1970. Merck also chose to complete pneumococcal vaccine clinical trials in South Africa and reported that their 6 and 12-valent vaccines reduced pneumococcal pneumonia disease rates by 76 and 92 percent respectively. 

Merck applied for a license to manufacture and market a 14-valent pneumococcal capsular polysaccharide vaccine, PNEUMOVAX, in 1976 and received FDA approval for the vaccine on November 21, 1977.  In January 1978, the CDC’s Advisory Committee on Immunization Practices (ACIP) recommended that the new pneumococcal vaccine be administered to all children and adults aged two and older with chronic health conditions which included sickle cell anemia, splenic dysfunction, diabetes mellitus, and chronic renal, lung, liver, and kidney disease. The vaccine was also approved for use during a pneumococcal outbreak involving a closed population, such as a nursing home or similar institution. 

Lederle, another established vaccine manufacturer, had also begun research and development for a pneumococcal polysaccharide vaccine in the 1970s and in August 1979, PNU-IMUNE, its 14-valent pneumococcal vaccine, received FDA approval. 

By the early 1980s, pneumococcal experts recognized the need to expand the number of pneumococcal strains contained within the polysaccharide vaccine to improve coverage on a global scale. The World Health Organization (WHO) along with the governments of several countries, reported that a 23-valent pneumococcal vaccine would provide better protection against pneumococcal disease worldwide.

In 1983, both Merck and Lederle introduced pneumococcal polysaccharide vaccines (PPV23) containing 23 strains of pneumococcal which were believed to cause approximately 87 percent of all bacterial pneumonia cases in the United States. The PPV23 vaccines were reformulated to contain 25mcg of each specific antigen, a decrease from the 50mcg per antigen found in the 14-valent vaccine, in an attempt to better balance safety and immune response. 

The CDC’s Advisory Committee on Immunization Practices (ACIP) voted in 1984 to recommend that all adults 65 and older receive a dose of PPV23 vaccine. This recommendation was made despite two separate studies showing that the vaccine was ineffective at reducing pneumococcal infections and deaths.   The CDC also continued to recommend that all adults and children aged two and older with chronic illness or immunosuppression receive a dose of the vaccine. 

In 1997, PPV23 recommendations were updated to include special populations such as individuals living in nursing homes and other long-term care facilities and for use in Alaskan Natives and certain American Indian populations. 

As pneumococcal polysaccharide vaccines were found to be ineffective in children under the age of two, vaccine development continued.  Pneumococcal related deaths were reported to be uncommon among children except in the case of immune suppression, meningitis, or severe bacteremia following the removal of the spleen, but children two and under, along with adults 65 and older, were still considered by health officials to be at a higher risk for pneumococcal infections. 

Development of a method to bind a polysaccharide with a carrier protein to enhance the immune response began in 1980, and in 1987, the conjugated Hib vaccine became the first vaccine using polysaccharide-protein conjugation technology to receive approval by the FDA. 

Wyeth Lederle was the first vaccine manufacturer to develop a pneumococcal conjugate vaccine, Prevnar 7. In pre-licensing clinical trials, Prevnar 7 (PCV7) was tested against an experimental meningitis C vaccine,  an “active” control that called into question the scientific validity of the trial. The vaccine, however, still received approval by the FDA in February of 2000. 

The 7-valent pneumococcal conjugate vaccine contained Streptococcus pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F, each of which are individually conjugated to diphtheria CRM197 protein and were 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 from the strains found within the vaccine. 

On June 21, 2000, the CDC’s ACIP voted to recommend PCV7 vaccine for use in all children 23 months of age and younger, as well as in children ages 24 to 59 months considered to be at high-risk of serious pneumococcal infection. 

The highly successful promotion by Wyeth Lederle, the CDC, and the American Academy of Pediatrics (AAP) made Prevnar (PCV7) the best-selling new pharmaceutical product of 2000, generating $461 million in sales. 

By 2001, however, PCV7’s popularity, in conjunction with manufacturing issues, resulted in vaccine shortages. The shortages required ACIP to temporarily revise PCV7 vaccine recommendations, prioritizing the vaccine’s use for children most at risk for pneumococcal disease.  Issues with vaccine shortages were not completely resolved until September of 2004. 

In October 2002, the FDA approved PCV7 for use in the prevention of middle ear infections (otitis media) despite clinical studies noting the vaccine to be only seven percent effective against all types of acute otitis media.   

Following PCV7 introduction on a global scale, scientists began to report that while the vaccine appeared to be effective in reducing nasopharyngeal carriage of S. pneumoniae strains found within the vaccine, this reduction had resulted in a significant increase in non-vaccine type strains,  most notably, strain 19A, a highly virulent and antibiotic-resistant serotype.    In Spain, an increase in invasive pneumococcal disease occurred following the introduction of PCV7, with the emergence of several non-vaccine type strains.     

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

Recommendations for the use of PCV13 were promptly issued by the CDC to essentially recommend that PCV13 be used in lieu of PCV7. Prior to FDA approval PCV13 was studied for safety in less than 4,800 healthy infants and toddlers and the vaccine was compared to infants and children receiving PCV7, alone or in combination with other vaccines. 

The CDC also recommended PCV13 for children and teenagers between 6 and 18 years of age not previously vaccinated and considered to be at high risk for pneumococcal disease related to immunosuppressive conditions including sickle cell anemia, asplenia, HIV, the presence of a cochlear implant, or cerebrospinal fluid leak.    At the time of this recommendation in December of 2010, the FDA had not approved the vaccine for use in children over the age of 59 months and did not expand the approval of the PCV13 vaccine for children and teenagers between the ages of 6 and 17 until January of 2013. 

In December of 2011, the FDA approved the expanded use of PCV13 under an “Accelerated Approval” process to include adults 50 years of age and older.  The “Accelerated Approval” process allows products targeted to treat a serious condition or fill an unmet need the opportunity to receive quicker FDA approval based on laboratory tests or other measurements believed to possibly predict a clinical benefit. 

In this case, a comparison was made between antibody responses of individuals receiving either PCV13 or Merck’s 23-valent pneumococcal polysaccharide vaccine (PPSV23). PCV 13 was found to have a similar or higher antibody response when compared to PPSV23 and the FDA permitted this laboratory finding to fulfill the requirement needed to receive “Accelerated Approval”, despite knowing that the level of vaccine-induced antibodies required to protect an individual against a particular strain of pneumococcal infection was unknown.   

While the ACIP declined to routinely recommend PCV13 for adults over the age of 50 following the FDA’s approval to expand its usage,  the committee did vote to recommend the vaccine for use in immunocompromised adults 19 years of age and older, in June of 2012.  The FDA, however, did not approve PCV13 for use in adults 19 to 49 until July 11, 2016. 

In 2014, the CDC updated its recommendations for the use of PCV13 and recommended that the vaccine be administered to all seniors 65 and older in addition to the previously recommended PPSV23 vaccine;  however, by October 2018, it was reported during an ACIP meeting that this recommendation had not reduced pneumonia rates among persons 65 years and older. 

In June 2019, ACIP voted to pull back from its 2014 recommendation and stated that healthy seniors 65 and older could consider this vaccination after discussions with their physician. PCV13 was still recommended for seniors 65 years and older who had chronic health conditions and a single dose of PPSV23 was still recommended for all persons 65 and older. 

Pneumococcal strains not covered within the vaccine have continued to emerge since the introduction of PCV13. Researchers in the United States have noted that while invasive pneumococcal disease has decreased since the introduction of pneumococcal conjugate vaccines, S. pneumoniae strains have adapted and antibiotic resistant non-vaccine strains have emerged.  These non-vaccine type strains include strains 33F, 22F, 12, 15B, 15C, and 23 A. 

Korea,   Taiwan,  and several Western European countries,   have also reported an increase in pneumococcal strains not covered by PCV13 and scientists continue to recommend pneumococcal strain monitoring and further development of vaccines in response to continued emergence of non-vaccine type strains.          

In June 2021, Wyeth pharmaceuticals received FDA approval for Prevnar 20 (PCV20) vaccine, a 20-valent pneumococcal conjugate vaccine, which added seven additional strains (8, 10A, 11A, 12F, 15B, 22F, and 33F) to the PCV13 vaccine. The vaccine was approved to be administered as a single dose in adults 18 years of age and older. 

Merck Sharp & Dohme Corp. received FDA approval for VAXNEUVANCE (PCV15) vaccine, a 15-valent pneumococcal conjugate vaccine, in July 2021. The vaccine was approved to be administered as a single dose in adults 18 years of age and older for prevention of invasive disease caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F and 33F. 

On October 20, 2021, ACIP voted to recommend that all adults 65 years of age and older who had not previously received a dose of pneumococcal conjugate vaccine be given a dose of PCV15 or PCV20. If PCV15 is administered, the CDC recommended that a dose of PPSV23 be given one year or more following administration of PCV15. The interval, however, could be shortened to eight weeks in persons with immunocompromising conditions.  Individuals aged 19 through 64 years with pre-existing health conditions that put them at an increased risk of invasive pneumococcal disease and who had not previously received a dose of pneumococcal conjugate vaccine were also recommended vaccination with PCV15 or PCV20. 

On June 17, 2022, the FDA licensed VAXNEUVANCE (PCV15) for use in individuals six weeks and older.  Five days later, on June 22, 2022, the CDC’s ACIP voted to approve the vaccine in individuals under the age of 19 years as an option to PCV13 in accordance with the current recommended pneumococcal conjugate vaccine schedule. 

The FDA approved Prevnar 20 (PCV20) in April 2023 for use in individuals six weeks of age and older for the prevention of invasive disease caused by S. pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F, and 33F and in infants and children aged six weeks through five years of age, for the prevention of otitis media (ear infection) caused by S. pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F.  The approval of the vaccine was based on clinical trials that compared both the safety and immune responses in healthy children who received PCV20 to those who received PCV13.  In June 2023, the CDC recommended PCV20 for use as an option to PCV13 and PCV15 according to the currently recommended pneumococcal vaccine schedule for healthy infants and children. PCV20 was also recommended for use in children aged two through 18 years at increased risk for pneumococcal disease. 

In June 2024, the FDA approved CAPVAXIVE (PCV21), manufactured by Merck, for the prevention of invasive disease caused by S. pneumoniae serotypes 3, 6A, 7F, 8, 9N, 10A, 11A, 12F, 15A,15B, 15C, 16F, 17F, 19A, 20A, 22F, 23A, 23B, 24F, 31, 33F, and 35B and for the prevention of pneumonia caused by S. pneumoniae serotypes 3, 6A, 7F, 8, 9N, 10A, 11A, 12F, 15A, 15C, 16F, 17F, 19A, 20A, 22F,23A, 23B, 24F, 31, 33F, and 35B in individuals 18 years of age and older.  According to the CDC, CAPVAXIVE targets 81 percent of the most commonly seen pneumococcal serotypes among adults. On June 27, 2024, the CDC’s ACIP voted to recommend CAPVAXIVE as an option for use in adults 19 years and older for whom a pneumococcal conjugate vaccine has been recommended.