Can immunologic memory be outpaced by meningococcal disease pathogenesis?
BY MICHAEL E. PICHICHERO, MD
credit: Steve Debenport/E+/Getty Images
The pace of pathogenesis for Neisseria meningitidis infection is very rapid. In a matter of hours bacteria can attach to epithelial cells of the nasopharynx and then gain entry to the blood and lymphatics. From there the bacteria seed multiple sites such as skin and vital organs. The result is meningococcemia and, in some cases, meningococcal meningitis. The consequences are dire, with loss of limb and life.
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Importance of antibodies
All vaccines against N. meningitidis work by the induction of antibodies in serum. Transudation from serum may block adherence of the bacteria to epithelial cells in the nasopharynx to prevent contagion spread and provide herd immunity. Serum bactericidal antibody levels of greater than or equal to 1:4 correlate with protection. However, a specific level of antibody is not an absolute correlate of protection for every person because there is genetic variation in susceptibility to disease, there can be differences in virulence among strains, there can be differences in innate immune responses among individuals, there can be variation in the inoculum of the pathogen, and there may be effects from concurrent illness or coinfection. Therefore, a specified protective level of antibody should be considered as a close estimate applicable in the majority of potentially susceptible persons.
Antibody levels usually decline over time after vaccination if boosters are not given, although there are exceptions. Persistence of vaccine-induced antibodies usually goes well beyond the time when antibodies should have disappeared according to the mathematics of their half-life. This may be caused by ongoing “natural” boosting or other immunologic mechanisms. Natural boosting can occur by asymptomatic colonization by the pathogen or by a nonpathogen expressing a cross-reactive antigen. Natural boosting can decrease over time as a pathogen circulates less widely in a population because of increasing use of a vaccine and/or the establishment of herd immunity. This is an ongoing issue relative to several vaccines because the absence of natural boosting among vaccinees may lead to a return to disease susceptibility.
Dr. Michael E. Pichichero
While many of the components of the immune response triggered by vaccination are known, the immune components that are needed to sustain a protective immune response are not fully understood. Vaccines that activate multiple antigen-presenting cell subsets through a diverse array of Toll-like receptors produce immunity that is more durable. The combination of receptor activation induces a set of proinflammatory cytokines that affect the Th1/Th2 helper cell balance and provides a strong stimulus for B-cell and T-cell memory. This is especially true in the case of the conjugate vaccines in which the naked polysaccharide of the bacteria is poorly immunogenic in very young children. However, conjugation of the polysaccharide with a protein activates T cells to help the B-cells in producing antibodies to the polysaccharide.
The production of memory B cells and T cells is a complex developmental process. The likelihood that a B-cell or T-cell memory response will be fast enough in the absence of a protective circulating antibody level likely depends in large part on the pace of pathogenesis of the infection caused by a specific organism.
The speed of production of measurable antibody responses following memory B-cell stimulation has been measured for N. meningitidis. A detectable response occurs 2-7 days following exposure. It takes that amount of time for antibody production because the bacteria must be taken up and processed by antigen presenting cells, then these cells must interact with B cells and T cells, then the B cells must proliferate and mature to plasma cells, and finally the plasma cells release the antibodies into circulation. Even if the antigen directly activates memory B cells by interaction with the B-cell receptor and no T-cell help is necessary, the memory B cell still takes time to process the antigen and mature to an antibody-secreting plasma cell.
Credit: © 2018 National Meningitis Association. All rights reserved.
In 2015, the CDC’s Advisory Committee on Immunization Practices issued a category B recommendation to vaccinate against MenB in individuals aged 16-23 years to provide short-term protection against most strains of serogroup B meningococcal disease.
In the United Kingdom after the introduction of meningococcal conjugate vaccines, a drop in antibody occurred as expected over time after the vaccination was given. Even though immunologic memory could be shown to persist, breakthrough cases of disease were observed. This led authorities in the United Kingdom to revise their vaccination program to require booster doses of meningococcal conjugate vaccines.
In the United States, the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices has recommended since 2005 the routine vaccination against N. meningitidis serogroups A, C, W, and Y for individuals aged 11-18 years. There were no N. meningitidis serotype B (MenB) vaccines available until 2014. There are now two vaccines (Bexero and Trumenba) that were licensed under the accelerated approval of biological products regulations for use in individuals aged 10-25 years. This approval was granted with the caveat that postmarketing clinical studies would be performed in order to further investigate the immunogenicity and tolerability of the products and to assess effectiveness in the targeted population in the United States. In 2015, the CDC’s Advisory Committee on Immunization Practices issued a category B recommendation to vaccinate against MenB in individuals aged 16-23 years to provide short-term protection against most strains of serogroup B meningococcal disease.
The Bexsero vaccine (GlaxoSmithKline) combines conserved, highly immunogenic, surface-expressed protein antigens (factor H–binding protein, NadA, and Neisserial heparin-binding antigen) with an outer membrane vesicle preparation, previously used successfully to help control a clonal MenB outbreak in New Zealand.
The human serum bactericidal assay for measuring functional antibody levels was used as the immunological correlate of protection and acceptance for licensure. At the time of licensure, limited information regarding the length of protection against disease was available. However, data on antibody persistence after Bexsero vaccination continue to accumulate.
For example, in a study of adolescent vaccinees, antibody levels were measured 18-23 months after a two-dose series: When measured for three of the four test strains, as many as 94%, 82%, and 77% of the subjects had protective titers to each of the three strains (Santolaya et al.Hum Vaccin Immunother. 2013 Nov 1; 9:2304-10).
The immunogenicity of Bexsero among adult laboratory staff using the recommended schedule of two doses at a 5-week interval was assessed. Immunogenicity was evaluated 6 weeks and 1 year after the second dose. All participants showed an increase in their bactericidal titers against the components of Bexsero 6 weeks after the second dose; however, titers declined significantly 1 year later (Hong et al. Hum Vaccin Immunother. 2017 Mar;13:645-8).
The Trumenba vaccine (Pfizer) consists of two variants of factor H–binding protein, one from subfamily A and one from subfamily B. It was licensed in the United States in October 2014 for use in individuals aged 10-25 years, with a three-dose schedule administered over a 6-month period. Recently, a two-dose schedule with the two doses administered 6 months apart has been licensed.
In a study of adult health care workers, three doses of Trumenba elicited short-term protective SBA responses to diverse disease-causing serogroup B strains. For some strains, serum titers declined to 1:4 by 9-11 months, which raised concerns about the duration of broad, long-term protection (Lujan et al. Clin Vaccine Immunol. 2017 Aug 4. doi: 10.1128/CVI.00121-17).
There are currently no data I am aware of on the persistence of the immune response following a booster dose of N. meningitidis serogroup B vaccine, but this will be examined in ongoing trials.
In a study of adolescents, after three doses of Trumenba, protective serum bactericidal assay titers above the correlate of protection (greater than or equal to 1:4) were elicited up to 4 years after the vaccination series in more than 50% of participants for three of four meningococcal serogroup B test strains representative of disease-causing meningococci that express vaccine-heterologous antigens (Marshall et al. Lancet Infect Dis. 2017 Jan;17:58-67).
Studies investigating the persistence of the immune response elicited by Trumenba found that there is a decline in antibodies over the 6-12 months following the last vaccine dose, after which the decline levels off (Shirley and Taha. Drugs. 2018 Feb;78:257-68). Substantial increases in antibody responses against all primary test strains were observed following a booster dose of Trumenba administered 4 years after the primary series, increases that were consistent with induction of immunological memory. There was no clear benefit of a three-dose series over a two-dose series in terms of the persistence of antibodies or the response to a booster dose.
Given the persistence data and given that circulating serum antibodies are considered necessary to convey protection against invasive meningococcal disease (with immunological memory alone not likely to be sufficient), some authorities recommended that, following a primary vaccination series, a booster dose of N. meningitidis serogroup B vaccine should be considered for individuals at continued risk of invasive meningococcal disease. The appropriate timing of a booster dose would be dependent on several factors, including the declining antibody titers, the local epidemiology and the antigen expression of circulating strains, and the possible effects of herd immunity. There are currently no data I am aware of on the persistence of the immune response following a booster dose of N. meningitidis serogroup B vaccine, but this will be examined in ongoing trials.
The antibody waning measured in the studies of Bexsero and Trumenba make it clear that the effective duration of protection following vaccination may be relatively short lived. It generally requires about 2-7 days for B memory cells and T memory cells to expand and give rise to increases in antibody levels on exposure to N. meningitidis. The innate immune system and preexisting circulating antibody levels must prevent progression of disease until memory responses occur. For N. meningitidis serogroup B in which the pace of pathogenesis is rapid, some individuals will contract infection before the memory response is fully activated and implemented. This is an area of active research for the future.
Dr. Pichichero, a specialist in pediatric infectious diseases, is director of the Research Institute at Rochester (N.Y.) General Hospital. He has no relevant financial disclosures. Email him at firstname.lastname@example.org.