Dan M. Granoff (born January 22, 1944) is an infectious disease physician-scientist who was named the 2014 Maurice Hilleman/Merck Laureate by the American Society for Microbiology for outstanding contributions to vaccine discovery and development. [1] Beginning in 2011, Granoff held the Clorox Foundation Endowed Chair and was director of the Center of Immunobiology and Vaccine Development at Children's Hospital Oakland Research Institute [2] (now known as University of California San Francisco (UCSF) Benioff Children's Hospital Oakland). His work increased understanding of basic mechanisms of human immunity to encapsulated bacteria, and furthered development of vaccines against Haemophilus influenzae type B (Hib) [3] and Neisseria meningitidis (also called the meningococcus). [4] [5] [6]
Granoff was born in 1944 in New York City, NY, [7] He divides his time between San Francisco, California, and Carmel Valley, California, with his partner, Marjory A Kaplan, [8] a retired lawyer. He was married to Alice Baghdassarian Granoff, M.D., [9] and divorced in 1985. They have two sons.
Granoff completed his bachelors and medical degrees at Johns Hopkins University, Baltimore Maryland. [2] He completed pediatric residency training at the Johns Hopkins Hospital, followed by a post-doctoral fellowship in pediatric infectious diseases at Case Western Reserve University School of Medicine, Cleveland Metropolitan General Hospital (now MetroHealth Medical Center).
Described below are some of Granoff’s most important research contributions.
In 1987, the first Hib conjugate vaccine, which used Hib capsular polysaccharide (called PRP) conjugated to diphtheria toxoid as the carrier protein, was licensed in the United States and recommended for the age group 18 to 60 months. [3] Granoff and colleagues were the first to test this vaccine in humans. [10] In subsequent studies with Dr. Trudy Virginia Noller Murphy then at Southwestern Medical School in Dallas TX, and Dr. Michael Osterholm, then at the Minnesota Department of Health, they demonstrated that the vaccine, called PRP-D, [3] not only decreased Hib disease in vaccinated children but also in children in the age group less than 18 months, which at the time was not being vaccinated. [11] [12] This study was one of the first to suggest that introduction of a polysaccharide-protein conjugate vaccine could lead to "herd immunity", [13] now also called “community protection” or "community immunity").
Granoff and his colleagues also demonstrated an unexpected decrease in the presence of Hib in the noses and throats of healthy children who had been immunized with PRP-D, when compared to unvaccinated children or children who had been vaccinated with an earlier Hib vaccine containing only unconjugated polysaccharide. [14] This finding provided a basis for the observed community protection against Hib disease in unvaccinated infants [15] (because of decreased exposure). [3]
In 1986 Granoff and his colleagues reported that a single injection of a modified Hib conjugate vaccine that used an meningococcal outer membrane complex as its carrier protein elicited a protective antibody response in two month-old infants. [16] This result was unexpected since scientists at the time believed that two-month-olds did not have mature B cells capable of responding to polysaccharide antigens. [17] [18] Granoff’s findings, which were subsequently confirmed by others, [5] [19] proved that B cells, with the appropriate rearranged genes, were present at age two months and were activated by a single injection of this Hib polysaccharide conjugate vaccine. [20] The presence of a meningococcal porin protein (called PorB) as part of the carrier protein likely provided unique adjuvant and immunostimulatory signals. [21] The adjuvant activity helps explain the unique ability of this Hib vaccine (now called PedVaxHib) to be immunogenic in 2 month olds after a single injection.
With Dr. Alexander H. Lucas, Granoff also used idiotype analysis to investigate variable region gene diversity in human antibodies for Hib polysaccharide. [22] They found dramatic changes in gene utilization by age of vaccination, and different Hib conjugate vaccine types. Collectively these studies contributed to making anti-Hib capsular antibodies one of the best understood human antibody systems at a molecular level. [23] [24]
For much of the 20th century, Sub-Saharan Africa experienced large epidemics of meningococcal disease caused by serogroup A strains. [25] By the mid-1990s, three vaccine manufacturers were developing meningococcal conjugate vaccines against serogroup C strains in response to public health concerns in the United Kingdom resulting from approximately 10,000 cases and 1000 deaths during the previous decade. [26] However, because of poor prospects for a profit, there was little interest by commercial manufacturers to develop a serogroup group A meningococcal conjugate vaccine for use in Sub-Saharan Africa where, during the same time period, there were more than 700,000 cases and 100,000 deaths. [25] In 1999, Granoff, working with colleagues at the World Health Organization, proposed developing and manufacturing a low cost, meningococcal vaccine for Africa using a public–private partnership. [26] [27] With funding by the Bill and Melinda Gates Foundation, and under the leadership of Dr. Marc LaForce, a low cost, vaccine, called MenAfriVac, was developed and introduced in Sub-Saharan Africa in 2010. [28] By 2015, more than 150 million people had been immunized. The vaccine has been highly effective in preventing group A epidemics and helped establish herd immunity. [28]
The polysaccharide protein conjugate vaccine approach used to develop successful Hib vaccines was subsequently applied to develop vaccines for prevention of meningococcal disease, a severe and often deadly infection of infants and teenagers. These efforts resulted in several licensed conjugate vaccines for prevention of disease caused by meningococcal strains with capsular groups designated A, C, Y and W . However, this approach was not feasible for a vaccine against group B strains, which were the most common cause of meningococcal disease in infants in North America and Europe. [5] The reason was that the group B capsule shares structural features that are similar to sugars present in human tissues. [29] Thus, stimulating antibodies to this bacterial capsule was difficult and if successful risked eliciting autoantibodies that could give rise to autoimmune disease. [5] Granoff, collaborating with Sanjay Ram's Laboratory, then at Boston University School of Medicine, and their colleagues identified a meningococcal lipoprotein that was critical for the ability of the bacteria to survive in human serum. [30] [31] The protein bound human complement factor H (FH), which is present in high concentrations in human serum, and down-regulates complement activation. The lipoprotein, which had been previously identified as a vaccine antigen of unknown function by two groups, had been designated GNA1870 by one group [32] or Lp2086 by another. [33] To reflect its function, Granoff and Ram renamed the lipoprotein "Factor H binding protein" or "FHbp". FHbp is now the main or sole antigen in the two meningococcal group B vaccines licensed in the U.S., Europe and in other areas of the world. [5] In immunized humans, however, the FHbp antigen forms a complex with human FH. [34] With Drs. Peter Beernink and Sanjay Ram, Granoff showed that FH binding to FHbp decreased protective antibody responses. [35] [36] Beernink and Granoff went on to create mutant FHbp vaccines with amino acid substitutions that decreased FH binding, which elicited greater protective antibody responses than antigens that bound FH. [37] They showed that currently licensed FHbp-based meningococcal B vaccines can be improved by introducing these amino acid substitutions. Granoff and his colleagues also investigated over-expressing FHbp in meningococcal native outer membrane vesicles (NOMV) prepared from mutant meningococcal strains. [38] In mice and infant macaque monkeys, the mutant meningococcal NOMV vaccine combined with over-expressing mutant low FH-binding FHbp elicited much higher and broader protective antibody responses than control vaccines, including a currently licensed one. [39] [40]
Granoff authored or co-authored more than 225 research articles in peer-reviewed journals and review articles, [41] and multiple textbook chapters including recent chapters on meningococcal vaccines published in the 7th and 8th editions of Plotkin’s Vaccines. [5] Granoff also co-edited a textbook on Hib vaccines with Dr. Ronald D Ellis. [42]
Granoff served as Professor of Pediatrics and Director of the Division of Pediatric Infectious Diseases at Washington University School of Medicine and St. Louis Children’s Hospital from 1979 to 1993. [2] In 1993, he became Executive Director of Clinical Vaccine Research at Chiron Corporation (Emeryville CA) with a joint appointment as a Scientist at Children’s Hospital Oakland Research Institute [2] (Currently UCSF Benioff Children’s Hospital)]. His team at Chiron was responsible for clinical development of the first adjuvanted influenza vaccine, [43] and a meningococcal serogroup C conjugate vaccine, [44] [3] which was used to control deadly outbreaks in the United Kingdom. [45] In 1995 Granoff became Vice President of Scientific Affairs. [2] He left Chiron in 1998 to become a Senior Scientist at Children’s Hospital Oakland Research Institute. Beginning in 2011, Granoff held the Clorox Foundation Endowed Chair and was Director of the Center of Immunobiology and Vaccine Development until his retirement in 2019.
Granoff served as associate editor of the journal, Pediatric Research from 1982 to 1988 [46] and is a member of the editorial boards of Human Vaccines & Immunotherapeutics [47] and the journal Vaccine. [48] He is a member on the editorial advisory board of the journal, Clinical Infectious Diseases . [49]
The American Society for Clinical Investigation (ASCI): Elected to membership in 1987 [50]
The American Academy of Microbiology: Elected as a Fellow in 2010 [51]
The Infectious Diseases Society of America and the Pediatric Infectious Diseases Society: Elected as a Fellow to both organizations.
Granoff is inventor or co-inventor on multiple US and international patents including Patent Nos. US6,936,261; US8,968,748; US9,034,345; US9,439,957; US10,857,221; and US10,905,754 and others. [55]
Neisseria is a large genus of bacteria that colonize the mucosal surfaces of many animals. Of the 11 species that colonize humans, only two are pathogens, N. meningitidis and N. gonorrhoeae.
Haemophilus influenzae is a Gram-negative, non-motile, coccobacillary, facultatively anaerobic, capnophilic pathogenic bacterium of the family Pasteurellaceae. The bacteria are mesophilic and grow best at temperatures between 35 and 37 °C.
Asplenia refers to the absence of normal spleen function and is associated with some serious infection risks. Hyposplenism is used to describe reduced ('hypo-') splenic functioning, but not as severely affected as with asplenism.
A conjugate vaccine is a type of subunit vaccine which combines a weak antigen with a strong antigen as a carrier so that the immune system has a stronger response to the weak antigen.
The bacterial capsule is a large structure common to many bacteria. It is a polysaccharide layer that lies outside the cell envelope, and is thus deemed part of the outer envelope of a bacterial cell. It is a well-organized layer, not easily washed off, and it can be the cause of various diseases.
Rino Rappuoli is an Italian immunologist. He is the head of vaccine research and development (R&D) at GlaxoSmithKline (GSK) Vaccines. Previously, he has served as visiting scientist at Rockefeller University and Harvard Medical School and held roles at Sclavo, Vaccine Research and CSO, Chiron Corporation, and Novartis Vaccines.
Neisseria meningitidis, often referred to as the meningococcus, is a Gram-negative bacterium that can cause meningitis and other forms of meningococcal disease such as meningococcemia, a life-threatening sepsis. The bacterium is referred to as a coccus because it is round, and more specifically a diplococcus because of its tendency to form pairs.
Meningococcal disease describes infections caused by the bacterium Neisseria meningitidis. It has a high mortality rate if untreated but is vaccine-preventable. While best known as a cause of meningitis, it can also result in sepsis, which is an even more damaging and dangerous condition. Meningitis and meningococcemia are major causes of illness, death, and disability in both developed and under-developed countries.
The Haemophilus influenzae type B vaccine, also known as Hib vaccine, is a vaccine used to prevent Haemophilus influenzae type b (Hib) infection. In countries that include it as a routine vaccine, rates of severe Hib infections have decreased more than 90%. It has therefore resulted in a decrease in the rate of meningitis, pneumonia, and epiglottitis.
John Bennett Robbins was a senior investigator at the National Institutes of Health (NIH), best known for his contribution to the development of the vaccine against bacterial meningitis Hib)) with his colleague Rachel Schneerson. He conducted research on the Bethesda, Maryland campus of the NIH from 1970 until his retirement at the age of 80 in 2012. During his tenure, he worked in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the Food and Drug Administration’s biologics laboratories on location.
NmVac4-A/C/Y/W-135 is the commercial name for a polysaccharide vaccine that protects against meningococcal meningitis caused by Neisseria meningitidis, specifically the serotypes A, C, Y, and W-135. This vaccine is part of a broader group of meningococcal vaccines. It is especially formulated for use in developing countries, aimed at protecting populations during meningitis outbreaks, particularly in high-risk regions like the African meningitis belt.
Meningococcal vaccine refers to any vaccine used to prevent infection by Neisseria meningitidis. Different versions are effective against some or all of the following types of meningococcus: A, B, C, W-135, and Y. The vaccines are between 85 and 100% effective for at least two years. They result in a decrease in meningitis and sepsis among populations where they are widely used. They are given either by injection into a muscle or just under the skin.
Haemophilus meningitis is a form of bacterial meningitis caused by the Haemophilus influenzae bacteria. It is usually associated with Haemophilus influenzae type b. Meningitis involves the inflammation of the protective membranes that cover the brain and spinal cord. Haemophilus meningitis is characterized by symptoms including fever, nausea, sensitivity to light, headaches, stiff neck, anorexia, and seizures. Haemophilus meningitis can be deadly, but antibiotics are effective in treating the infection, especially when cases are caught early enough that the inflammation has not done a great deal of damage. Before the introduction of the Hib vaccine in 1985, Haemophilus meningitis was the leading cause of bacterial meningitis in children under the age of five. However, since the creation of the Hib vaccine, only two in every 100,000 children contract this type of meningitis. Five to ten percent of cases can be fatal, although the average mortality rate in developing nations is seventeen percent, mostly due to lack of access to vaccination as well as lack of access to medical care needed to combat the meningitis.
George Rainer Siber is a Canadian-American medical researcherand vaccinologist.
Rachel Schneerson is a former senior investigator in the Laboratory in Developmental and Molecular Immunity and head of the Section on Bacterial Disease Pathogens and Immunity within the Laboratory at the Eunice Kennedy Shriver National Institute of Child Health and Human Development within the National Institutes of Health. She is best known for her development of the vaccine against bacterial meningitis with her colleague John B. Robbins.
CRM197 is a non-toxic mutant of diphtheria toxin, currently used as a carrier protein for polysaccharides and haptens to make them immunogenic. There is some dispute about the toxicity of CRM197, with evidence that it is toxic to yeast cells and some mammalian cell lines.
A hexavalent vaccine, or 6-in-1 vaccine, is a combination vaccine with six individual vaccines conjugated into one, intended to protect people from multiple diseases. The term usually refers to the children's vaccine that protects against diphtheria, tetanus, pertussis, poliomyelitis, haemophilus B, and hepatitis B, which is used in more than 90 countries around the world including in Europe, Canada, Australia, Jordan, and New Zealand.
Janet Gilsdorf is an American pediatric infectious diseases physician, scientist, and writer at the University of Michigan. Her research has focused on the pathogenic, molecular, and epidemiologic features of the bacterium Haemophilus influenzae. She served as the Director of the Division of Pediatric Infectious Diseases in the University of Michigan Health System from 1989 to 2012 and Co-Director of the Center for Molecular and Clinical Epidemiology of Infectious Diseases at the School of Public Health at the University of Michigan from 2000 – 2015. In addition to her scientific publications, she is also the author of two novels, one memoir, one non-fiction book, and a number of medically-oriented essays.
Trudy Virginia Noller Murphy is an American pediatric infectious diseases physician, public health epidemiologist and vaccinologist. During the 1980s and 1990s, she conducted research at Southwestern Medical School in Dallas, Texas on three bacterial pathogens: Haemophilus influenzae type b (Hib), Streptococcus pneumoniae (pneumococcus), and methicillin-resistant Staphylococcus aureus (MRSA). Murphy's studies advanced understanding of how these organisms spread within communities, particularly among children attending day care centers. Her seminal work on Hib vaccines elucidated the effects of introduction of new Hib vaccines on both bacterial carriage and control of invasive Hib disease. Murphy subsequently joined the National Immunization Program at the Centers for Disease Control and Prevention (CDC) where she led multi-disciplinary teams in the Divisions of Epidemiology and Surveillance and The Viral Hepatitis Division. Among her most influential work at CDC was on Rotashield™, which was a newly licensed vaccine designed to prevent severe diarrheal disease caused by rotavirus. Murphy and her colleagues uncovered that the vaccine increased the risk of acute bowel obstruction (intussusception). This finding prompted suspension of the national recommendation to vaccinate children with Rotashield, and led the manufacturer to withdraw the vaccine from the market. For this work Murphy received the United States Department of Health and Human Services Secretary's Award for Distinguished Service in 2000, and the publication describing this work was recognized in 2002 by the Charles C. Shepard Science Award from the Centers for Disease Control and Prevention.
Penbraya is a pentavalent conjugate vaccine developed by Pfizer for the prevention of invasive meningococcal disease in people 10 through 25 years of age. Invasive meningococcal disease, caused by the bacterium Neisseria meningitidis, can lead to serious conditions such as meningitis and sepsis. Penbraya is approved for use by the US Food and Drug Administration (FDA). Penbraya is the first pentavalent vaccine that provides coverage against the five most common serogroups causing meningococcal disease.