Almost all current vaccines work by the induction of antibodies in serum or on the mucosa to block adherence of pathogens to epithelial cells or interfere with microbial invasion of the bloodstream. However, antibody levels usually decline after vaccination to undetectable amounts if further vaccination does not occur. Persistence of vaccine-induced antibodies usually goes well beyond the time when they should have decayed to undetectable levels because of ongoing “natural” boosting or other immunologic mechanisms. The production of memory B and T cells is of clear importance, but the likelihood that a memory response will be fast enough in the absence of a protective circulating antibody level likely depends on the pace of pathogenesis of a specific organism. This concept is discussed with regard to Haemophilus influenzae type b, Streptococcus pneumoniae, and Neisseria meningitidis; hepatitis A and B; diphtheria, tetanus, and pertussis; polio, measles, mumps, rubella, and varicella; rotavirus; and human papilloma virus. With infectious diseases for which the pace of pathogenesis is less rapid, some individuals will contract infection before the memory response is fully activated and implemented. With infectious diseases for which the pace of pathogenesis is slow, immune memory should be sufficient to prevent disease.
- immunologic memory
- Neisseria meningitides
- Haemophilus influenzae type b
- human papilloma virus
With the introduction of so many new vaccines over the past decade and many more on the horizon, clinicians are often asked, or wonder themselves, whether boosters for all these vaccines will be necessary down the road. Sentinel study populations have been established by vaccine companies as phase 4 postlicensure evaluations to forewarn public health authorities and practitioners if such boosters will be needed. In this review I will present information on what is known about B-cell and T-cell immune memory and innate immunity and the pace of pathogenesis for the diseases we are currently preventing with vaccination, and I will examine the dynamic nature of the situation as changes in natural boosting occur.
IMPORTANCE OF ANTIBODIES
As observed by Robbins et al1 and Plotkin,2 almost all current vaccines work by the induction of antibodies in serum or on the mucosa (by local production or transudation from serum) to block adherence of pathogens to epithelial cells or interfere with microbial invasion of the bloodstream. To protect, the induced antibodies must either be functional against the relevant pathogen or aid the immune system as an opsonin, or, if the organism exerts its pathogenic effect by elaborating a toxin, then the antibodies must neutralize that toxin.2 The importance of antibodies in vaccine-induced protection is undeniable, as supported by studies in which passive administration prevents or ameliorates disease and the observation of a protective effect in the newborn by maternal antibody.3 All maternal protection of the fetus and newborn occurs as a result of antibodies, because maternal B cells and T cells do not cross the placenta.
Specific levels of antibody have been correlated with protection against many diseases (Table 1). The levels of antibody that correlate with protection are generally derived from population studies wherein observations have been made that individuals with a certain level of antibody are always or nearly always protected from disease. However, a specific level of antibody is not an absolute correlate of protection for every person, because it is not only the quantity of antibody that is important but also the functionality of the antibody. Also, there is genetic variation in susceptibility to disease, differences in virulence among pathogen strains, differences in innate immune responses among individuals, and variation in the inoculum of the pathogen, and there may be an impact from concurrent illness or coinfection. Therefore, a specified protective level of antibody should be considered as a close estimate applicable in the majority of hosts as a relative correlate of protection.
Antibody levels usually decline to undetectable amounts over time if further antigen stimulation does not occur, because antibodies have a half-life of ∼30 days. However, persistence of vaccine-induced antibodies usually goes well beyond the time when the antibodies should have disappeared according to the mathematics of their half-life. This may be a result of ongoing “natural” boosting or other immunologic mechanisms discussed below.
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 vaccine recipients may lead to a return to disease susceptibility.
Other explanations have been proposed for the persistence of low levels of circulating antibodies long after antigen exposure has occurred. One hypothesis is that small amounts of antigen are retained and persist inside peripheral lymph nodes and spleen. The small amount of antigen is enough to keep the immune response ongoing.4 A second hypothesis suggests that some memory B cells become sequestered in the bone marrow sanctuary, where they periodically divide, mature to plasma cells, and produce small amounts of antibody in serum.5 A third hypothesis is that nonspecific polyclonal B-cell activators maintain a continuous, small memory B-cell pool. The hypothesized nonspecific B-cell activators include several microbial products that stimulate Toll-like receptors (TLRs) (discussed later) and may also occur through bystander T-cell help.6,7
ROLE OF MEMORY B CELLS
The production of memory B cells is a complex developmental process that occurs in lymph node and spleen germinal centers. During the generation of memory B cells a selection process occurs called affinity maturation.8 As antigen becomes less and less available after vaccination, random mutations of immunoglobulin genes occur and the B cells expressing antibodies on their surface with the highest affinity for the diminishing vaccine antigen win out and persist as memory B cells. There is a strong correlation between highly functional antibody and antibody with high affinity for a vaccine antigen. The features of vaccine-induced B-cell–mediated immune memory are (1) a rapid production of antibody, (2) predominately immunoglobulin G antibody, (3) a higher antibody level than occurred after primary exposure, and (4) production of antibody of higher affinity (and an antibody population of higher avidity) for the antigen as a result of a process known as affinity maturation.
To assess the duration of immune memory, vaccinated subjects provide serum and lymphoid cells for in vitro analysis at time intervals after vaccination. Persistence of antibody levels, B memory cells, and T memory cells can then be measured. The best tool for assessing immune memory is to perform challenge experiments whereby a one-fifth to one-tenth standard antigen dose is given to the test subjects, and then the immune response is evaluated. This simulation is not perfect, because (1) we do not know the actual pathogen-specific antigen dose, (2) delivery of the antigen by the parenteral route is clearly not the same as the reality in nature, where nearly all exposures occur via the skin, respiratory, gastrointestinal, or genitourinary tracts, and (3) the context of the simulation is not during a concurrent illness (eg, a viral upper respiratory infection, as often occurs in nature).
T-cell immunity plays a role in terminating disease or maintaining protection against disease over time. Indeed, T-cell–dependent and antibody-independent mechanisms of protection against infections were recently described in mice9–11 and in man.12 Cell immunity is a term often used synonymously with T-cell immunity.
Two memory T-cell populations are now known to exist. Effector memory T cells reside in peripheral tissues, whereas another pool, termed central memory T cells, reside in lymphoid organs.13 Both memory T-cell populations express surface proteins that make them distinguishable from naive T cells.14 The continuous circulation of effector memory T cells into tissue is a key feature of the immune system that ensures that memory T cells of particular specificities are disseminated throughout the body.
It is well established that memory CD4+ T cells respond more quickly and with a wider array of cytokines and that memory CD8+ T cells respond with the release of a greater quantity of cytotoxic molecules (perforin and granzyme B) than occurs during a primary response.12 Also, memory CD4+ T cells are more effective at helping B cells compared with naive CD4 T cells.15,16
A faster and broader memory T-cell response has the potential to control infection quickly after reexposure to pathogens.17–19 In both CD4 and CD8 in vitro models the generation of T-cell effector functions (cell-mediated immunity) can be evident ∼2 to 7 days after antigen stimulation.20–23 The maintenance of T-cell memory varies according to the antigen. T-cell memory after vaccination with small protein fragments is much shorter than that achieved after vaccination with an attenuated but replicating virus.24–27
In addition to adaptive immunity, the pace of pathogenesis can be slowed by the innate immune response.28 New information over the past decade has revealed that the innate immune system has developed a strategy to recognize conserved structures of microbes that are not present on mammalian cells: so-called pathogen-associated molecular patterns.29 Also, a recognition and signaling system called TLRs has been described, which initiates a cascade of immunologic events in human host cells to contain infection, giving the adaptive immune response time to respond.30,31 TLR2 is a receptor for lipoteichoic acid of Gram-positive bacteria, bacterial lipoproteins, and zymosan (yeasts); TLR3 is a receptor for viral double-stranded DNA; TLR4 is a receptor for lipopolysaccharides of Gram-negative bacteria; and TLR9 is a receptor for bacterial DNA.32,33 Once the TLRs are stimulated by the pathogen-associated molecular patterns, immunologic effector cells do not need to proliferate or mature; they can immediately respond by releasing multiple proinflammatory and antiinflammatory mediators and cytokines. Because it takes 2 to 7 days for sufficient amounts of antibodies and effector T cells to be produced, the host relies on the innate immune system to hold the infection in check temporarily. If the innate response is not adequate, then infection may occur despite immune memory.
OUTPACING INFECTION WITH AN IMMUNE RESPONSE
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 (Table 2). Several examples are described below to illustrate this point.
Haemophilus influenzae Type b, Streptococcus pneumoniae, and Neisseria meningitidis
The pace of pathogenesis for encapsulated respiratory bacteria such as Haemophilus influenzae type b (Hib), Streptococcus pneumoniae, and Neisseria meningitidis is very rapid. In a matter of hours bacteria can adhere to the nasopharynx, gain entry to the bloodstream, replicate, and begin to seed the meninges. Infection by these encapsulated bacteria is prevented by the presence of functional antibody directed to the polysaccharide capsule.
The speed of production of measurable antibody responses after memory B-cell stimulation has been measured for Hib and meningococcus.34–37 In both cases a detectable response was observed no sooner than 2 to 7 days after antigen exposure. It takes some time from antigen exposure to antibody production, because the antigen must be taken up and processed by antigen-presenting cells (eg, dendritic cells and macrophages); then, the antigen-presenting cells must interact with B cells and helper T cells, the B cells must proliferate and mature to plasma cells, and, finally, the plasma cells release antibody into the circulation.
After introduction of the Hib conjugate vaccines, a debate emerged on the protective role of immune memory in the absence of detectable antibody.38 This occurred with the introduction of diphtheria-tetanus-acellular pertussis (DTaP) vaccines combined with Hib conjugate vaccines, because several DTaP-Hib combination vaccines did not produce as high of an antibody level as administration of the 2 separate vaccines.39,40 The debate ended when Hib disease began to occur in England and Wales, where DTaP-Hib combinations were licensed and researchers showed that a circulating level of functional antibody was necessary for long-term protection for some children.41–43 This same scenario was repeated again in the United Kingdom after the introduction of meningococcal conjugate vaccines. A decrease in antibody despite persistence of immunologic memory was associated with a decline in vaccine effectiveness.44–46 As a result of the breakthrough cases of disease, the United Kingdom revised its vaccination program to require booster doses of Hib and meningococcal conjugate vaccines so as to maintain protective antibody levels in the blood.
After the primary vaccination series in infancy is completed for Hib conjugates, only 1 booster is needed in the second year of life to afford protection until ∼5 years of age. This is because during the third through the fifth year of life children develop “natural” immunity to Hib induced by colonization of their gastrointestinal tract by a species of Escherichia coli that expresses a polysaccharide capsule (K1 capsule) nearly identical to the Hib polysaccharide capsule47 (Fig 1). Natural antibody also is produced to meningococci and pneumococci, but it is currently unknown whether the frequency of development of such natural antibody will be sufficient to supplement vaccine-induced immunity. The sporadic occurrence of meningococcal and pneumococcal disease throughout life speaks to the likelihood for the need for boosters.
Hepatitis B and A
The pace for pathogenesis of hepatitis B and hepatitis A pathogenesis is slow. Clinically, before hepatitis B and hepatitis A vaccines became available, the administration of passive antibody in the form of intramuscular γ globulin could be done 2 weeks after exposure and still be effective. Immunity to hepatitis B and A is lifelong after natural infection.
Hepatitis B vaccine–induced antibody levels wane over time such that by 10 years after vaccination only approximately one third of vaccine recipients still have detectable antibody levels.48 Nevertheless, up to now there has been no breakthrough disease. This success has been attributed to memory antibody responses that occur in sufficient time to afford protection after exposure (Fig 2). However, a recent report of the persistence of immunologic memory 15 to 18 years after hepatitis B vaccination raises concerns.49 Less information is available about persistence of immunity and immune memory after hepatitis A vaccination, because it was introduced more recently.
Diphtheria, Tetanus, and Pertussis
Diphtheria, tetanus, and pertussis are diseases caused by release of toxins; there is no bacteremia. The pace of pathogenesis is several days (diphtheria and tetanus) to several weeks (pertussis) between infection and the elaboration of sufficient toxin to manifest as disease. Natural infection does not confer lifelong protection from any of these 3 diseases. Memory responses to tetanus have been shown to occur after a time lag of several days to 2 weeks.50
Breakthrough cases of diphtheria in the former Soviet Union produced an epidemic in the 1980s that included many vaccinated individuals.51 Breakthrough cases of tetanus are well known to occur among vaccine recipients, thus leading to the recommended every-10-year booster.52 Waning immunity has been demonstrated to occur after use of whole-cell pertussis vaccines,53–56 leading to adolescent and adult cases among vaccinated individuals57–59 and likely will occur in the future after acellular pertussis vaccines if boosters are not given. In terms of pathogenesis one might predict that the prolonged prodrome of pertussis, generally 1 to 3 weeks of upper respiratory–like symptoms before cough illness begins, should be sufficient in length to allow immune memory to outpace disease. However, this does not occur most likely because replication of the organism is only on the mucosal surface (not in the bloodstream) and the organism itself does not elicit a vigorous inflammatory/ immunologic response when it is present in the tracheobronchial tree. Perhaps only with the elaboration of sufficient pertussis toxin does the immune system become stimulated.
Polio, Measles, Mumps, Rubella, and Varicella
Polio, measles, mumps, rubella, and varicella are characterized by 2 viremic phases during pathogenesis. A first viremia occurs 2 to 4 days after exposure, and then there is a 1- to 3-day hiatus followed by a second and larger viremic stage during which wider dissemination of the virus occurs. Thereafter, the onset of prodrome symptoms occurs, followed by the classical manifestations of disease. Permanent immunity is acquired after natural infection.
For polio, measles, mumps, rubella, and varicella, the pace of pathogenesis may be sufficiently slow to allow immune memory responses to intervene and prevent the important, disease-causing second viremic phase in most individuals. Booster doses of polio, measles, mumps, rubella, and varicella vaccines are not currently recommended, but waning immunity has been raised as a concern.60–64 Additional doses of these vaccines have been suggested to produce immunity among a relatively small cohort of individuals who fail to respond to primary vaccination.65,66 Live, attenuated strains as opposed to killed viral vaccines more closely mimic natural infection where immunity is known to be lifelong. It is possible that reactivation of latent vaccine virus induces boosts in antibody levels. The duration of immunity from enhanced inactivated polio vaccine is under prospective study.67
Natural rotavirus infections are not fully protective, although reinfections are uniformly milder in severity than primary infections.68 The 2 currently available rotavirus vaccines are live attenuated reassortant vaccines. The pace of pathogenesis of rotavirus involves several days from infection to disease. Although immunity may be incomplete after infection and may wane after vaccination, it is unlikely that boosters will be recommended in later childhood, because the infection rate is much lower in older children.
Human Papilloma Virus
The mechanism of protection after human papilloma virus (HPV) vaccination seems to be the production of neutralizing antibody.69–72 The pace of pathogenesis for HPV in humans is not known. In animal models it takes 30 minutes to 24 hours73–77 for the virus to gain entry to the basal epithelial cells (and infect the cell); thereafter, the virus becomes largely inaccessible to antibody. Therefore, it would seem that a minimum level of antibody would need to be present in mucus (whether locally produced or as a result of transudation from serum) at the time of exposure to prevent infection (Fig 3). After HPV vaccination, it is currently uncertain whether “natural” cervical HPV infection would be sufficient to stimulate a protective antibody response (natural boosting).78–83 Although the role of immune memory remains uncertain, high and sustained neutralizing antibody titers are considered to be the best surrogate marker for protection from HPV infection after vaccination.84
It generally requires ∼2 to 5 days for B memory cells and T memory cells (cell-mediated immunity) to expand and give rise to mature immune effector cells after a host experiences exposure to a potential pathogen. The innate immune system and preexisting circulating antibody levels must prevent progression of disease until memory responses occur. With infectious diseases for which the pace of pathogenesis is rapid, some individuals will contract infection before the memory response is fully activated and implemented. With infectious diseases for which the pace of pathogenesis is slow, immune memory should be sufficient to prevent disease. For some newer vaccines there is uncertainty whether breakthrough infections will occur. This is an area of active research that will provide answers to this important question in the future.
- Accepted June 15, 2009.
- Address correspondence to Michael E. Pichichero, MD, Rochester General Research Institute, Rochester General Hospital, 1425 Portland Ave, Rochester, NY 14621. E-mail:
Financial Disclosure: The author has indicated he has no financial relationships relevant to this article to disclose.
- ↵Robbins JB, Schneerson R, Szu S. Perspective: hypothesis—serum IgG antibody is sufficient to confer protection against infectious diseases by inactivating the inoculum. J Infect Dis.1995;171 (6):1387– 1398
- ↵Plotkin SA. Vaccines: correlates of vaccine-induced immunity. Clin Infect Dis.2008;47 (3):401– 408
- ↵Bachmann MT, Odermat B, Hengertner H, Zinkernagel RM. Induction of long-lived germinal centers associated with persisting antigen after viral infection. J Exp Med.1996;183 (5):2259– 2269
- ↵Bernasconi N, Traggiai E, Lanzavecchia A. Maintenance of serological memory by polyclonal activation of human memory B cells. Science.2002;298 (5601):2199– 2202
- ↵McCool TL, Weiser JN. Limited role of antibody in clearance of Streptococcus pneumoniae in a murine model of colonization. Infect Immun.2004;72 (10):5807– 5813
- Malley R, Trzcinski K, Srivastava A, Thompson CM, Anderson PW, Lipsitch M. CD4+ T cells mediate antibody-independent acquired immunity to pneumococcal colonization. Proc Natl Acad Sci USA.2005;102 (13):4848– 4853
- ↵Trzcinski K, Thompson CM, Srivastava A, Basset A, Malley R, Lipsitch M. Protection against nasopharyngeal colonization by Streptococcus pneumoniae is mediated by antigen-specific CD4+ T cells. Infect Immun.2008;76 (6):2678– 2684
- ↵Zhang Q, Bagrade L, Bernatoniene J, et al. Low CD4 T cell immunity to pneumolysin is associated with nasopharyngeal carriage of pneumococci in children [published correction appears in J Infect Dis. 2008;197(9):1354]. J Infect Dis.2007;195 (8):1194– 1202
- ↵Okada R, Kondo T, Matsuki F, Takata H, Takiguchi M. Phenotypic classification of human CD4+ T cell subsets and their differentiation. Int Immunol.2008;20 (9):1189– 1199
- ↵Croft M, Swain SL. Analysis of CD4+ T cells that provide contact-dependent bystander help to B Cells. J Immunol.1992;149 (10):3157– 3165
- ↵Bradley LM, Duncan DD, Tonkonogy SL, Swain SL. Characterization of antigen-specific CD4+ effector T cells in vivo: immunization results in a transient population of MEL−14−, CD45RB-helper cells that secretes interleukin 2 (IL-2), IL-3, IL-4, and interferon gamma. J Exp Med.1991;174 (3):547– 559
- Swain SL, Weinberg AD, English M, Huston G. IL-4 directs the development of Th2-like helper effectors. J Immunol.1990;145 (11):3796– 3806
- Azuma M, Cayabyab M, Phillips JH, Lanier LL. Requirements for CD28-dependent T cell-mediated cytotoxicity. J Immunol.1993;150 (6):2091– 2101
- ↵Bradley LM, Duncan DD, Yoshimoto K, Swain SL. Memory effectors: a potent, IL-4 secreting helper T cell population that develops after restimulation with antigen. J Immunol.1993;150 (8 pt 1):311 9–3130
- ↵Gray D, Matzinger P. T cell memory is short-lived in the absence of antigen. J Exp Med.1991;174 (5):969– 974
- Oehen S, Waldner H, Kundig TM, Hengartner H, Zinkernagel RM. Antivirally protective cytotoxic T cell memory to lymphocytic choriomeningitis virus is governed by persisting antigen. J Exp Med.1992;176 (5):1273– 1281
- ↵Netea MG, Vand der Meer JWN, Sutmuller RP, Adema GJ, Kullberf B. From the Th1/Th2 paradigm towards a Toll-like receptor/T-helper bias. Antimicrob Agents Chemother.2005;49 (10):3991– 3996
- Snape MD, Kelly DF, Salt P, et al. Serogroup C meningococcal glycoconjugate vaccine in adolescents: persistence of bactericidal antibodies and kinetics of the immune response to a booster vaccine more than 3 years after immunization. Clin Infect Dis.2006;43 (11):1387– 1394
- ↵Tsai TF, Borrow R, Gnehm E, et al. Early appearance of bactericidal antibodies after polysaccharide challenge of toddlers primed with a group C meningococcal conjugate vaccine: what is its role in the maintenance of protection? Clin Vaccine Immunol.2006;13 (8):854– 861
- ↵Rennels MB, Englund J, Bernstein D, et al. Diminution of the anti-polyribosylribitol phosphate response to a combined diphtheria-tetanus-acellular pertussis/Haemophilus influenzae type b vaccine by concurrent inactivated poliovirus vaccination. Pediatr Infect Dis J.2000;19 (5):417– 422
- ↵McVernon J, Johnson PD, Pollard AJ, Slack MP, Moxon ER. Immunologic memory in Haemophilus influenzae type b conjugate vaccine failure. Arch Dis Child.2003;88 (5):379– 383
- Oh SY, Griffiths D, John T, et al. School-aged children: a reservoir for continued circulation of Haemophilus influenzae type b in the United Kingdom. J Infect Dis.2008;197 (9):1275– 1281
- ↵Yeh CL, Kelly D, Ly-Mee Y, et al. Haemophilus influenzae type b vaccine failure in children is associated with inadequate production of high-quality antibody. Clin Infect Dis.2008;46 (2):186– 192
- ↵Lin YC, Chang MH, Ni YH, Hsu HY, Chen DS. Long-term immunogenicity and efficacy of universal hepatitis b virus vaccination in Taiwan. J Infect Dis.2003;187 (1):134– 138
- ↵Lu CY, Ni YH, Chiang BL, et al. Humoral and cellular immune responses to a hepatitis B vaccine booster 15–18 years after neonatal immunization. J Infect Dis.2008;197 (10):1419– 1425
- Jansen DL, Gray GC, Putnam SD, Lynn F, Meade BD. Evaluation of pertussis in U.S. Marine Corps trainees. Clin Infect Dis.1997;25 (5):1099– 1107
- Cattaneo LA, Reed GW, Haase DH, Wills MJ, Edwards KM. The seroepidemiology of Bordetella pertussis infections: a study of persons ages 1–65 years. J Infect Dis.1996;173 (5):1256– 1259
- ↵Esposito S, Agliardi T, Giammanco A, et al. Long-term pertussis-specific immunity after primary vaccination with a combined diphtheria, tetanus, tricomponent acellular pertussis, and hepatitis B vaccine in comparison with that after natural infection. Infect Immun.2001;69 (7):4516– 4520
- ↵Mancuso JD, Snyder A, Stigers J, et al. Pertussis outbreak in a US military community: Kaiserslauten, Germany, April–June 2005. Clin Infect Dis.2007;45 (11):1476– 1478
- Gilberg S, Njamkepo E, Parent du Chatelet I, et al. Evidence of Bordetella pertussis infection in adults presenting with persistent cough in a French area with very high whole-cell vaccine coverage. J Infect Dis.2002;186 (3):415– 418
- Asano Y, Nagai T, Miyata T, et al. Long-term protective immunity of recipients of the OKA strain of live varicella vaccine. Pediatrics.1985;75 (4):667– 671
- ↵Lopez AS, Guris D, Zimmerman L, et al. One dose of varicella vaccine does not prevent school outbreaks: is it time for a second dose? Pediatrics.2006;117 (6). Available at: www.pediatrics.org/cgi/content/full/117/6/e1070
- Roden RB, Kirnbauer, Booy FP, Jessie J, Lowy DR, Schiller JT. In vitro generation and type-specific neutralization of a human papillomaviruses with the cell surface. J Virol.1996;70 (9):5875– 5883
- Wang Z, Christensen N, Schiller JT, Dillner J. A monoclonal antibody against intact human papillomavirus type 16 capsids blocks the serological reactivity of most human sera. J Gen Virol.1997;78 (pt 9):2209– 2215
- ↵Day PM, Gambhira R, Roden RBS, Lowy DR, Schiler JT. Mechanisms of human papillomavirus type 16 neutralization by l2 cross-neutralizing and l1 type-specific antibodies. J Virol.2008;82 (9):4638– 4646
- Sibbet G, Romero-Graillet C, Meneguzzi G, Campo MS. α 6 integrin is not the obligatory cell receptor for bovine papillomavirus type 4 [published correction appears in J Gen Virol. 2000;81(pt 6):1629]. J Gen Virol.2000;81 (pt 2):327– 334
- Ozbun MA. Infectious human papillomavirus type 31b: purification and infection of an immortalized human keratinocyte cell line. J Gen Virol.2002;83 (pt 11):2753– 2763
- Carter JJ, Koutsky LA, Hughers JP, et al. Comparison of human papillomavirus types 16, 18, and 6 capsid antibody responses following incident infection. J Infect Dis.2000;181 (6):1911– 1919
- Ho GYF, Studentsov YY, Bierman R, Burk RD. Natural history of human papillomavirus type 16 virus-like particle antibodies in young women. Cancer Epidemiol Biomarkers Prev.2004;13 (1):110– 116
- Prakash S, Patterson S, Kapembwa MS. Macrophages are increased in cervical epithelium of women with cervicitis. Sex Transm Infect.2001;77 (5):366– 369
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