Susan B. Manoff

Safety and Antibody Response, Including Antibody Persistence for 5 Years, after Primary Vaccination or Revaccination with Pneumococcal Polysaccharide Vaccine in Middle-Aged and Older Adults

BACKGROUND This study assessed antibody levels for 5 years after primary vaccination or revaccination with 23-valent pneumococcal polysaccharide vaccine (PN23). METHODS Subjects were enrolled into 4 study groups by age (50-64 or > or = 65 years) and prior vaccination status (no prior vaccination or 1 vaccination 3-5 years previously). Blood was obtained on day 0 (before primary vaccination or revaccination), day 30, day 60, and annually during years 2-5. Levels of immunoglobulin G (IgG) to 8 vaccine serotypes were measured by enzyme-linked immunosorbent assay. RESULTS Of 1008 enrolled subjects, 551 completed year 5. For each serotype and age group, baseline geometric mean concentrations (GMCs) of IgG were higher in revaccination than primary vaccination subjects. Primary vaccination or revaccination with PN23 induced significant increases in levels of antibody to all serotypes tested. Although day 30 and 60 antibody levels tended to be modestly lower after revaccination, study groups had similar GMCs at later time points. For serotypes 4, 6B, 8, 9V, 12F, 14, and 23F, GMCs during years 2-5 after primary vaccination or revaccination remained higher than in vaccine-naive persons. Levels of antibody to serotype 3 returned to baseline by year 2. CONCLUSIONS Both primary vaccination and revaccination with PN23 induce antibody responses that persist during 5 years of observation.

Revaccination with a 23-Valent Pneumococcal Polysaccharide Vaccine Induces Elevated and Persistent Functional Antibody Responses in Adults Aged ⩾65 Years

BACKGROUND Older adults are at high risk of developing invasive pneumococcal disease, but the optimal timing and number of vaccine doses needed to prevent disease among this group are unknown. We compared revaccination with 23-valent pneumococcal polysaccharide vaccine (PN23) with primary vaccination for eliciting initial and persistent functional antibody responses. METHODS Subjects aged > or = 65 years were enrolled. Functional (opsonic) and total immunoglobulin (Ig) G antibody levels were measured following either PN23 primary vaccination (n = 60) or revaccination 3-5 years after receiving a first PN23 vaccination (n = 60). Antibody against vaccine serotypes 4, 14, and 23F was measured at prevaccination (day 0), 30 days after vaccination, and 5 years after vaccination. RESULTS By day 30, both primary vaccination and revaccination induced significant increases in opsonic and IgG antibody levels. Day 30 levels following revaccination were slightly lower but not significantly different than those after primary vaccination. Year 5 levels were similar in both groups and remained significantly higher than prevaccination levels for primary vaccination subjects. There was good agreement between postvaccination opsonic and IgG antibody levels. CONCLUSIONS Revaccination of older adults with PN23 was comparable to primary vaccination for inducing elevated and persistent functional and IgG antibody responses.

Antibody persistence ten years after first and second doses of 23-valent pneumococcal polysaccharide vaccine, and immunogenicity and safety of second and third doses in older adults.

In a study of older adults, first and second doses of 23-valent pneumococcal polysaccharide vaccine (PN23) induced IgG increases for all 8 vaccine serotypes tested. Participants (N=143, mean age 76 years) were re-enrolled to study antibody levels after ten years, and safety and immunogenicity of another PN23 dose. Ten years after first or second doses, mean IgG concentrations exceeded vaccine-naïve levels for 7 of 8 serotypes tested. Second and third doses administered at this time were generally well tolerated and were immunogenic, inducing similar postvaccination levels. Immunogenicity is preserved after multiple PN23 doses without evidence of a lower than expected immune response (i.e., without hyporesponsiveness).

Safety and Immunogenicity of Heat-Treated Zoster Vaccine (ZVHT) in Immunocompromised Adults

BACKGROUND Safety and immunogenicity of heat-treated zoster vaccine (ZVHT) were assessed in immunocompromised adults. METHODS In a randomized, double-blind, placebo-controlled, multicenter study, 4 doses ZVHT or placebo were administered approximately 30 days apart to adults with either solid tumor malignancy (STM); hematologic malignancy (HM); human immunodeficiency virus (HIV) with CD4(+) ≤200; autologous hematopoietic stem-cell transplant (HCT) or allogeneic-HCT recipients. Varicella-zoster virus (VZV) T-cell responses by interferon-γ enzyme-linked immunospot (IFN-γ ELISPOT) and VZV antibody concentrations by glycoprotein enzyme-linked immunosorbent assay (gpELISA) were measured at baseline and approximately 28 days after each dose. RESULTS No safety signals were found in any group. IFN-γ ELISPOT geometric mean fold rises (GMFR) after dose 4 in STM, HM, HIV, and autologous-HCT patients were 3.00 (P < .0001), 2.23 (P = .004), 1.76 (P = .026), and 9.01 (P = NA), respectively. Similarly, antibody GMFR were 2.35 (P < .0001), 1.28 (P = .003), 1.37 (P = .017), and 0.90 (P = NA), respectively. T-cell and antibody responses were poor after 4 doses of ZVHT in allogeneic-HCT patients. CONCLUSION ZVHT was generally safe and immunogenic through 28 days post-dose 4 in adults with STM, HM, and HIV. Autologous-HCT but not allogeneic-HCT patients had a rise in T-cell response; antibody responses were not increased in either HCT population. Study identification. V212-002 Clinical Trials Registration. NCT00535236.

Measles, mumps, and rubella virus vaccine (M–M–R™II): A review of 32 years of clinical and postmarketing experience

M-M-R™II (measles, mumps, and rubella virus vaccine live; Merck, Sharp, & Dohme Corp.) is indicated for simultaneous vaccination against measles, mumps, and rubella in individuals ≥ 12 months of age. Before the vaccine era, these viruses infected most exposed individuals, with subsequent morbidity and mortality. One of the greatest achievements of public health has been to eliminate these 3 diseases in large geographic areas. The safety profile of M-M-R™II is described using data from routine global postmarketing surveillance. Postmarketing surveillance has limitations (including incomplete reporting of case data), but allows collection of real-world information on large numbers of individuals, who may have concurrent medical problems excluding them from clinical trials. It can also identify rare adverse experiences (AEs). Over its 32-year history, ≈ 575 million doses of M-M-R™II have been distributed worldwide, with 17,536 AEs voluntarily reported for an overall rate of 30.5 AEs/1,000,000 doses distributed. This review provides evidence that the vaccine is safe and well-tolerated.

Pneumococcal polysaccharide 23-valent vaccine: Long-term persistence of circulating antibody and immunogenicity and safety after revaccination in adults

Since publication of a 1997 review of the immunogenicity and safety data for pneumococcal polysaccharide vaccines (PPSVs), dozens of additional studies have been published, involving larger cohorts, longer observation periods, and more specific assays. Additionally, a 13-valent pneumococcal conjugate vaccine (PCV) has been licensed for adults. This paper reviews adult studies assessing antibody persistence for ≥ 3 years after pneumococcal vaccination, and adult studies of immunogenicity and safety after revaccination. This review emphasizes the currently registered PPSV23 formulations containing 25-μg polysaccharide per serotype, for which far more long-term data are available. Broadly, IgG and functional antibody levels after PPSV23 in adults persist above concentrations in unvaccinated adults for at least 5-10 years in most studies. The few exceptions involve populations of non-ambulatory adults or those with confounding host-factor issues. Revaccination with PPSV23 5-10 years after a previous dose consistently and substantially increases both IgG and functional antibody levels. There is an inverse association between circulating antibody level just before primary or revaccination and subsequent antibody increase. Although injection-site reactions (e.g., pain, swelling, redness) were reported more commonly after PPSV23 revaccination than after primary vaccination in most studies, these reactions typically resolved within 5 days. We interpret the contemporary literature as supporting pneumococcal revaccination as a means to sustain anti-pneumococcal antibodies at levels greater than among unvaccinated adults. PPSV23 is a broad-spectrum public-health tool to help prevent serious pneumococcal diseases across the adult lifespan.

Preclinical and clinical development of a dengue recombinant subunit vaccine

This review focuses on a dengue virus (DENV) vaccine candidate based on a recombinant subunit approach which targets the DENV envelope glycoprotein (E). Truncated versions of E consisting of the N-terminal portion of E (DEN-80E) have been expressed recombinantly in the Drosophila S2 expression system and shown to have native-like conformation. Preclinical studies demonstrate that formulations containing tetravalent DEN-80E adjuvanted with ISCOMATRIX™ adjuvant induce high titer virus neutralizing antibodies and IFN-γ producing T cells in flavivirus-naïve non-human primates. The preclinical data further suggest that administration of such formulations on a 0, 1, 6 month schedule may result in higher maximum virus neutralizing antibody titers and better durability of those titers compared to administration on a 0, 1, 2 month schedule. In addition, the virus neutralizing antibody titers induced by adjuvanted tetravalent DEN-80E compare favorably to the titers induced by a tetravalent live virus comparator. Furthermore, DEN-80E was demonstrated to be able to boost virus neutralizing antibody titers in macaques that have had a prior DENV exposure. A monovalent version of the vaccine candidate, DEN1-80E, was formulated with Alhydrogel™ and studied in a proof-of-principle Phase I clinical trial by Hawaii Biotech, Inc. (NCT00936429). The clinical trial results demonstrate that both the 10 μg and 50 μg formulations of DEN1-80E with 1.25 mg of elemental aluminum were immunogenic when administered in a 3-injection series (0, 1, 2 months) to healthy, flavivirus-naïve adults. The vaccine formulations induced DENV-1 neutralizing antibodies in the majority of subjects, although the titers in most subjects were modest and waned over time. Both the 10 μg DEN1-80E and the 50 μg DEN1-80E formulations with Alhydrogel™ were generally well tolerated.

Advances in the understanding, management, and prevention of dengue

Dengue causes more human morbidity globally than any other vector-borne viral disease. Recent research has led to improved epidemiological methods that predict disease burden and factors involved in transmission, a better understanding of immune responses in infection, and enhanced animal models. In addition, a number of control measures, including preventative vaccines, are in clinical trials. However, significant gaps remain, including the need for better surveillance in large parts of the world, methods to predict which individuals will develop severe disease, and immunologic correlates of protection against dengue illness. During the next decade, dengue will likely expand its geographic reach and become an increasing burden on health resources in affected areas. Licensed vaccines and antiviral agents are needed in order to effectively control dengue and limit disease.

Pneumococcal vaccines in adults: Assessing the evolving evidence

Pneumococcal polysaccharide vaccines (PPSVs) are a publicealth success. Before their widespread use, people at increased isk for pneumococcal disease (e.g., some with advanced age, sickleell disease, or asplenia) developed fulminant pneumococcal sepsis, hich was often fatal. PPSV vaccination reduces morbidity and ssociated mortality [1–5]. Pneumococcal conjugate vaccines (PCVs) are another publicealth success. PCVs provide substantial direct benefits to infants nd young children, and help indirectly to reduce pneumococcal isease among adults [6]. PPSVs have been licensed for adults since 1977, and the 13alent PCV is likely to gain this status. In preparing for this ventuality, clinicians need to evaluate the accumulating evidence rom clinical studies of these vaccines among adults. Findings from nfants and young children cannot be generalized to older persons. neumococcal immune responses vary by age, immune compeence, and other factors. Unlike infants and young children, adults re rarely naive to Streptococcus pneumoniae, and thus are more ikely to have preexisting immunity to some serotypes. Adults are ess likely to have nasopharyngeal colonization. Unlike children < 2

Vaccination of adults with 23-valent pneumococcal polysaccharide vaccine induces robust antibody responses against pneumococcal serotypes associated with serious clinical outcomes

ABSTRACT PNEUMOVAX™ 23, a 23-valent polysaccharide pneumococcal vaccine (PPV23), covers 65% to 91% of the isolates recovered from adult cases of invasive pneumococcal disease. Several studies have demonstrated that pneumococcal serotypes 31, 11A, 35F, 17F, 3, 16F, 19F, 15B, and 10A are associated with higher case-fatality or meningitis rates than other pneumococcal serotypes. This study (U05-PnPS-403; EudraCT: 2008-003648-12) evaluated the immune response followings administration of PPV23 for 4 of these serotypes (10A, 11A, 15B, and 17F), that are included in PPV23 but not in licensed pneumococcal conjugate vaccines. Serotype-specific IgG geometric mean concentrations (GMCs) and geometric mean fold-rises (GMFRs) for these 4 serotypes were measured by a validated enzyme-linked immunosorbent assay (ELISA) in 104 subjects >50 y of age who were enrolled in a study evaluating the safety and immunogenicity of a single-dose of PPV23. At 1 month post-vaccination, GMCs for serotypes10A, 11A, 15B and 17F were 6.5, 4.3, 14.7, and 5.1 µg/mL, respectively. GMFRs from baseline were 9.0, 4.5, 8.4, and 11.5, respectively. The percentages of subjects achieving >2-fold increases in IgG GMCs between pre-vaccination and 1 month post-vaccination were 90%, 85%, 88% and 89%, respectively. In conclusion, PPV23 induces a robust immune response in adults to pneumococcal serotypes 10A, 11A, 15B, and 17F, which have been associated with elevated case-fatality or meningitis rates.