The Most Important Vaccine, 1980-2014

John G. Bartlett, MD

Editor's Note: This is the fifth installment of the Medscape Awards in Infectious Diseases, a series that honors the greatest achievements in the field of infectious diseases. In this article, John G. Bartlett, MD, Professor Emeritus of Medicine at Johns Hopkins University School of Medicine in Baltimore, Maryland, offers his choice for the most important vaccine developed since 1980. 

Vaccines

Vaccines are a remarkably effective preventive strategy in the field of infectious diseases. The power of this weapon (often referred to as the "pediatric vaccines") is illustrated in the Table, which shows Centers for Disease Control and Prevention (CDC) surveillance data for selected vaccine preventable diseases, comparing median annual disease rates before vaccine availability with recently reported results (2011-2014).

Table. Vaccine Efficacy

Hib = Haemophilus influenzae type b. From Centers for Disease Control and Prevention

Eradication and Reemergence

Measles was declared eradicated in 2002, but is now back, with a 20-year high in reported cases (554 cases from January 1 to July 3, 2014). Most cases have occurred in unvaccinated travelers, who then became sources of transmission when exposed to unvaccinated US natives.

Pertussis rates^[1] reflect the subpar protection that accompanied the shift to the acellular vaccine, but there is no going back.^[1] These data are misleading because pertussis severity is reduced in those who received the acellular vaccine.

Polio has been eliminated in the United States, but the global picture for polio eradication is grim, with the recent surge of cases in affected countries. None of these vaccines are considered for the Medscape Awards, because all were introduced before 1980.

The Candidate Vaccines

The candidates under consideration for the Medscape Award for most important vaccine developed since 1980 are those developed to prevent infections caused by Haemophilus influenzae type b (Hib), Streptococcus pneumoniae, hepatitis B virus (HBV), and human papillomavirus (HPV). Note that influenza vaccines are not considered because, although there is a new version nearly every year, the first was introduced in 1942 and there is no consensus about how well it works or whether it even works at all.

Questions answered incorrectly will be highlighted.

What do you think is the most important vaccine developed since 1980?

Pneumococcal vaccine

Human papillomavirus vaccine

Haemophilus influenzae type b vaccine

Hepatitis B virus vaccine

Other vaccine, not listed here (tell us about your choice in Comments)

Important Vaccines Since 1980

Pneumococcal Vaccine

The initial standard was the 23-valent polysaccharide vaccine, spearheaded by a the great leader in pneumococcal infections, Robert Austrian.^[2] The efficacy of this vaccine has been debated, but the consensus is that its major demonstrable benefit was protection against invasive pneumococcal infections, primarily bacteremia and meningitis.

The 7-valent protein-conjugated pneumococcal vaccine (Prevnar 7) was introduced in 2000 for pediatrics, and was considered superior to the polysaccharide vaccine. Prevnar® 7 has had an enormous impact on the distribution of serotypes in adults with invasive pneumococcal infections as well as in children, indicating a substantial herd immunity effect.^[3] The implication is that the child receives the injection, and the benefit is shared by the parents and grandparents.

This redistribution of predominant serotypes was associated with selected "escape strains" that were not included in the vaccine and became dominant in invasive pneumococcal infections in both children and adults. The major serotypes that emerged were 19A and 6C. This accounts for the introduction of Prevnar 13 in 2010, which includes serotypes 19A and 6C, as well as additional serotypes not covered by Prevnar 7.^[4]

These vaccines have been credited with the recent findings of reduced rates of serious pneumococcal infections, including an estimated reduction of 47,000 hospitalizations yearly in children and a reduction of 75,000 hospitalizations yearly for pneumococcal community-acquired pneumonia (CAP) in adults^[5] The polysaccharide vaccine is currently recommended in the United States for adults aged > 65 years and for those with selected predisposing conditions.^[6]

Prevnar 13 is US Food and Drug Administration (FDA)-approved for persons aged > 50 years, but is not recommended for adults except those who have selected immune deficiency states. This may change on the basis of the results of the CAPiTA trial of Prevnar 13, recently completed in the Netherlands. The just-released data from CAPiTA, which involved 85,000 adults aged 65 years or older, showed a 45% reduction in CAP cases involving vaccine serotypes.^[7] These data will be considered in making new recommendations for adult vaccinations in the United States. In terms of importance, the pneumococcal vaccines have had a major impact on invasive pneumococcal infections (especially bacteremia), on serotype distribution, and probably on the number of hospitalizations for CAP.

A continuing question is the importance of S pneumoniae in CAP in contemporary medicine. This microbe was identified as the cause of > 80% of adult cases of CAP, on the basis of robust data from thousands of patients in the prepenicillin era,^[8] and was called "captain of the men of death" by Osler.^[9] Ask any student or resident what causes CAP, and the predictable answer is S pneumoniae. However, it is not possible to find a published report from the United States in which this agent was identified as the cause in more than 10% of cases.^[10] (Higher rates are found in some other countries, possibly reflecting variations in national vaccine policies). A central question is whether the vaccine is a major or an incidental factor.

Human Papillomavirus Vaccine

The HPV vaccine was recommended by the Advisory Committee on Immunization Practices (ACIP) for females in 2006 and was extended to young men in 2009.^[6] The major target is cancer prevention -- primarily cervical, but also anal and oropharyngeal cancers.

HPV accounts for virtually all cases of cervical cancer (approximately 12,000 annually in the United States and 527,000 worldwide).^[11] The oncogenic strains are types 16 and 18. Infection is usually acquired shortly after sexual debut, so the recommendation for the vaccine series in most countries is age 10-14 years. HPV strains 16 and 18 also account for about 90% of anal cancers in both men and women -- a global total of about 28,000 cases yearly.^[12]

Two vaccine products are FDA-approved and CDC-recommended: the bivalent vaccine against the 2 carcinogenic HPV types (16 and 18), and the quadrivalent vaccine that adds protection against HPV types 6 and 11, which are the major causes of genital warts. The current CDC recommendation is a 3-dose series starting at age 11 or 12 years in boys and girls.^[6] Uptake in the United States has been slow, in large part owing to cost and inconvenience. Australia seems to have a model program in which the product is government-purchased and the vaccine is administered in schools.^[13]

Although these recommendations are only 5 years old, benefit has already been documented on the basis of a reduced rate of cervical dysplasia and a significant reduction in genital warts.^[14] HPV vaccines are an exciting development because they protect against an important cause of cancer. Unfortunately, the vaccine is unaffordable in developing countries, where rates of cervical cancer are extremely high and the need is greatest.

Haemophilus influenzae Type b Vaccine

Haemophilus influenzae was originally reported in 1892 by Dr. Pfeiffer, when it was known as "Pfeiffer's bacillus."^[15] It was later named "Haemophilus influenzae," when Dr. Pfeiffer assumed it caused influenza because it was recovered in sputum samples of patients with influenza. Ribotype b of H influenzae is the cause of 95% of serious H influenzae infections, primarily in children aged < 5 years.^[16] In the prevaccine era, this was a major pathogen in serious childhood infections in the United States and the world.

The Hib vaccine, which contains capsular material from type b strains, was introduced in 1985 for routine use after trials showed that vaccination prevents upper-airway colonization, which is the source of its major clinical expression.^[17] Before the vaccine was available, approximately 20,000 cases of invasive H influenzae occurred each year in the United States, primarily as meningitis in children < 5 years of age, but also as epiglottitis and pneumonia.^[18] Standard use of the vaccine in pediatric practice in the United States promptly resulted in a 98% reduction in invasive infections caused by this pathogen.

Seldom has the impact of a vaccine or treatment been so fast and profound. In 1980, any pediatric resident seeing a child < 5 years with meningitis would put H influenzae at the top of the differential list. In contemporary medical practice, many pediatric residents have never seen a case of invasive H influenzae infection. Unfortunately, the lack of this vaccine in developing countries is responsible for the World Health Organization estimate of 350,000-700,000 pediatric deaths annually caused by invasive H influenzae.^[19]

Hepatitis B Vaccine

The health consequences of HBV infection are legion. Worldwide, approximately 2 billion people have been infected, 240 million have chronic HBV infection, and 600,000 die annually from HBV liver disease -- either end-stage liver disease or hepatocellular carcinoma.^[20] The virus is transmitted perinatally, by unsafe injections, through unscreened blood transfusions, and by sexual contact, but not by food or water. These factors made vaccine development a high priority, but it wasn't easy. This virus was never successfully cultivated in artificial media, rendering the challenge unprecedented, yet the effort was successfully undertaken by Dr. Maurice Hilleman.

The initial vaccine was produced by isolating and purifying hepatitis B surface antigen (HBsAg), the "Australian antigen," so named because it was first recognized in Australian Aboriginal peoples. The initial effort, developed under leadership of Dr. Hilleman, involved harvesting surface antigen from the blood of chronic carriers.^[21] There was obvious concern about contaminants and a stormy incident suggesting transmission of HIV that proved to be erroneous. The second-generation HBV vaccine was produced by recombinant methods using transfected Saccharomyces cerevisiae, and became available in 1986. Third-generation tests followed in the 1990s using transfected mammalian cells, a product with enhanced immunogenicity.

By 2007, a total of 168 countries had either implemented or planned new universal HBV vaccination for newborns or adolescents. The model program was developed in Taiwan, where the incidence of HBV infection and hepatocellular cancer was extremely high. Their universal infant HBV vaccine policy reduced rates of this infection in children < 15 years of age from 9.8% in 1984 to 0.7% in 1999.^[22] In the United States, the rate of HBV infection in children fell from 40-100 per 1000 to 1.3 per 1000, a 30-fold reduction.^[23]

My Choice: Most Important Vaccine

Many would view this as a 2-horse race between the Hib vaccine and the HBV vaccine in terms of the challenge for product development, policy for use implementation, and documented impact. My selection is the HBV vaccine. Both vaccines have had a major impact on serious and common infectious diseases. My preference for HBV is based on some unique features:

• It is the only vaccine against a pathogen that has never been successfully cultivated in artificial media;
• It is the first vaccine for a sexually transmitted disease;
• It appears to have the greatest impact on mortality; and
• It is the first vaccine that prevents cancer.

References

1. Plotkin SA. The pertussis problem. Clin Infect Dis. 2014;58:830-833.
2. Austrian R. A brief history of pneumococcal vaccines. Drugs Aging. 1999;15 Suppl 1:1-10.
3. Griffin MR, Zhu Y, Moore MR, Whitney CG, Grijalva CG. U.S. hospitalizations for pneumonia after a decade of pneumococcal vaccination. N Engl J Med. 2013;369:155-163.
4. Sherwin RL, Gray S, Alexander R, et al. Distribution of 13-valent pneumococcal conjugate vaccine Streptococcus pneumoniae serotypes in US adults aged ≥50 years with community-acquired pneumonia. J Infect Dis. 2013;208:1813-1820.
5. Whitney CG, Farley MM, Hadler J, et al; Active Bacterial Core Surveillance of the Emerging Infections Program Network. Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine. N Engl J Med. 2003;348:1737-1746.
6. Bridges CB, Coyne-Beasley T; Advisory Committee on Immunization Practices. Advisory Committee on Immunization Practices recommended immunization schedule for adults aged 19 years or older: United States, 2014. Ann Intern Med. 2014;160:190-197.
7. Bonten M, Bolkenbaas M, Huijts S, et al. Community acquired pneumonia immunisation trial in adults (CAPITA). Program and abstracts of the 9th International Symposium on Pneumocci and Pneumococcal Diseases; March 9-13, 2014; Hyperabad, India. Abstract 0541.
8. Heffron R. Pneumonia. Cambridge, Mass: Harvard University Press; 1939:305.
9. White B. Biology of the Pneumococcus. Cambridge, Mass; Harvard University Press: 1938:7.
10. File TM, Low DE, Eckburg PB, et al; FOCUS 1 investigators. FOCUS 1: a randomized, double-blinded, multicentre, phase III trial of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in community-acquired pneumonia. J Antimicrob Chemother. 2011;66 Suppl 3:19-32.
11. Centers for Disease Control and Prevention (CDC). Recommendations on the use of quadrivalent human papillomavirus vaccine in males -- Advisory Committee on Immunization Practices (ACIP), 2011. MMWR Morb Mortal Wkly Rep. 2011;60:1705-1708.
12. Joseph DA, Miller JW, Wu X, et al. Understanding the burden of human papillomavirus-associated anal cancers in the US. Cancer. 2008;113(10 Suppl):2892-2900.
13. Young EJ, Tabrizi SN, Brotherton JM, et al. Measuring effectiveness of cervical cancer vaccine in an Australian setting (the VACCINE study). BMC Cancer. 2013;13:296.
14. Ali H, Donovan B, Wand H, et al. Genital warts among Australians five years into national human papillomavirus vaccination programme: national surveillance data. BMJ. 2013;346:f2032.
15. Chandran A, Watt JP, Santosham M. Prevention of Haemophilus influenzae type b disease: past success and future challenges. Expert Rev Vaccines. 2005;4:819-827.
16. Cochi SL Broome CV. Vaccine prevention of Haemophilus influenzae type b disease: past, present and future. Pediatr Infect Dis. 1986;5:12-19.
17. Black SB, Shinefield HR, Fireman B, Hiatt R, Polen M, Vittinghoff E. Efficacy in infancy of oligosaccharide conjugate Haemophilus influenzae type b (HbOC) vaccine in a United States population of 61,080 children. The Northern California Kaiser Permanente Vaccine Study Center Pediatrics Group. Pediatr Infect Dis J. 1991;10:97-104.
18. Briere EC, Rubin L, Moro PL, Cohn A, Clark T, Messonnier N; Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, CDC. Prevention and control of Haemophilus influenzae type b disease: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2014;63:1-14.
19. Global Programme for Vaccines and Immunization (GPV). The WHO position paper on Haemophilus influenzae type b conjugate vaccine. Wkly Epidemiol Rec. 1998;73:64-68.
20. Kao JH, Chen DS. Global control of hepatitis B infection. Lancet Infect Dis. 2002;2:395-403.
21. Zanetti AR, Van Damme P, Shouval D. The global impact of vaccination against hepatitis B: a historical overview. Vaccine. 2008;26:6266-6273.
22. Chien YC, Jan CF, Kuo HS, Chen CJ. Nationwide hepatitis B vaccination program in Taiwan: effectiveness in the 20 years after it was launched. Epidemiol Rev. 2006;28:126-135.
23. Daniels D, Grytdal S, Wasley A, Centers for Disease Control and Prevention (CDC). Surveillance for acute viral hepatitis -- United States, 2007. MMWR Surveill Summ. 2009;58:1-27.