Modeling Respiratory Syncytial Virus Adult Vaccination in the United States With a Dynamic Transmission Model.

BACKGROUND: Respiratory syncytial virus (RSV) is shown to cause substantial morbidity, hospitalization, and mortality in infants and older adults. Population-level modeling of RSV allows to estimate the full burden of disease and the potential epidemiological impact of novel prophylactics. METHODS: We modeled the RSV epidemiology in the United States across all ages using a deterministic compartmental transmission model. Population-level symptomatic RSV acute respiratory tract infection (ARI) cases were projected across different natural history scenarios with and without vaccination of adults aged ≥60 years. The impact of vaccine efficacy against ARIs, infectiousness and vaccine coverage on ARI incidence were assessed. The impact on medical attendance, hospitalization, complications, death, and other outcomes was also derived. RESULTS: Without a vaccine, we project 17.5-22.6 million symptomatic RSV ARI cases annually in adults aged ≥18 years in the US, with 3.6-4.8 million/year occurring in adults aged ≥60 years. Modeling indicates that up to 2.0 million symptomatic RSV-ARI cases could be prevented annually in ≥60-year-olds with a hypothetical vaccine (70% vaccine efficacy against symptomatic ARI and 60% vaccine coverage) and that up to 0.69 million/year could be prevented in the nonvaccinated population, assuming 50% vaccine impact on infectiousness. CONCLUSIONS: The model provides estimated burden of RSV in the US across all age groups, with substantial burden projected specifically in older adults. Vaccination of adults aged ≥60 years could significantly reduce the burden of disease in this population, with additional indirect effect in adults aged <60 years due to reduced transmissibility.

Erratum to: Frailty has a stronger association with inflammation than age in older veterans.

[This corrects the article DOI: 10.1186/s12979-016-0082-z.].

Influenza in the elderly: a mini-review.

Influenza is an important cause of morbidity and mortality in the elderly population each year. The often subtle clinical manifestations in the frail geriatric patients may not be recognized initially, impeding timely administration of antiviral treatment. The effectiveness of current influenza vaccines in the elderly population is often diminished by immune senescence. Increasing immunization rates among health-care workers and elderly caregivers, and finding more effective vaccines for the elderly people are likely to significantly improve disease prevention in this population at risk.

Long-term use of oseltamivir for the prophylaxis of influenza in a vaccinated frail older population.

OBJECTIVES: To investigate the efficacy of once-daily oral oseltamivir for 6 weeks (Tamiflu) in prophylaxis against laboratory-confirmed clinical influenza in frail older subjects living in homes for seniors and to determine the safety and tolerability of long-term oseltamivir. DESIGN: Double-blind, placebo-controlled, parallel-group, randomized, multicenter study. SETTING: Thirty-one residential homes for seniors across United States and Europe. PARTICIPANTS: Five hundred forty-eight frail older occupants (mean age 81 years, >80% vaccinated). INTERVENTION: Prophylaxis with oseltamivir 75 mg or placebo once daily for 6 weeks, beginning when influenza was detected locally. MEASUREMENTS: The primary efficacy endpoint was laboratory-confirmed clinical influenza. RESULTS: Oseltamivir administration resulted in a 92% reduction in the incidence of laboratory-confirmed clinical influenza compared with placebo (placebo 12/272 (4.4%), oseltamivir 1/276 (0.4%); P = .002). Of subjects vaccinated against influenza, oseltamivir was 91% effective in preventing laboratory-confirmed clinical influenza (placebo 11/218 (5.0%), oseltamivir 1/222 (0.5%); P = .003). Oseltamivir use was associated with a significant reduction in the incidence of secondary complications (placebo 7/272 (2.6%), oseltamivir 1/276 (0.4%); P = .037). Although nearly all subjects were taking concomitant medication both before and during the study, oseltamivir was well tolerated. A similar incidence of adverse events, including gastrointestinal effects, occurred in both groups. There was no suppression of antibody response in oseltamivir recipients. CONCLUSION: Oral oseltamivir 75 mg once daily for 6 weeks effectively prevented clinical influenza in vaccinated frail older subjects using significant concomitant medications in a residential care setting. The treatment was well tolerated and provided additional protection to that afforded by vaccination.

Granzyme B: a marker of risk for influenza in institutionalized older adults.

Risk for influenza increases with age while cellular immune responses decline. This was a prospective study to determine the relationship between cytokine and granzyme B levels in peripheral blood mononuclear cells stimulated with live influenza virus, and subsequent influenza illness. Granzyme B levels were lower in the group who later developed symptomatic laboratory-confirmed influenza (n=10) compared to the group who did not (n=90) (ANOVA, P=0.024). In contrast, none of the cytokine levels were related to the development of influenza. Thus, granzyme B is a potential marker of influenza risk in older adults.

Zanamivir: a review of clinical safety in individuals at high risk of developing influenza-related complications.

Post-marketing experience shows zanamivir to be well tolerated in the general population for the treatment and prophylaxis of influenza type A and B infections. Individuals at high-risk of influenza have potentially more to gain from zanamivir therapy. We assessed safety and tolerability findings from treatment and prophylaxis studies in over 982 high-risk subjects. Eight treatment studies involving high-risk subjects have been conducted with zanamivir 10 mg twice daily for 5 days. The incidence and pattern of adverse events was similar in zanamivir and placebo recipients. Lower respiratory adverse events reported by recipients receiving zanamivir occurred at similar or lower frequencies to those receiving placebo. In one treatment study involving 525 patients with asthma or chronic obstructive pulmonary disease, zanamivir recipients had a small but significantly increased mean morning peak expiratory flow rate (PEFR) and evening PEFR compared with placebo during the treatment period (days 1 to 5). Eight prophylaxis studies have been conducted, five in family or community settings and three in nursing homes. Data from these studies demonstrate that zanamivir is well tolerated for prophylaxis. In nursing home studies, where 90% of participants were high risk, the pattern and incidence of adverse events were similar to that reported in otherwise healthy individuals, and similar to both placebo and rimantadine, a comparator in one study. In treatment and prophylaxis studies the incidence and pattern of adverse events in participants > or =65 years or with chronic underlying respiratory disorders was similar for zanamivir or placebo recipients. Overall, zanamivir was well tolerated and study drug discontinuations were low. A small number of deaths have been reported in studies of high-risk elderly individuals, but none were considered to be related to zanamivir. Thus clinical studies have demonstrated that zanamivir has a comparable safety profile in high-risk and otherwise healthy recipients. Approximately 1.72 million treatment courses of zanamivir were prescribed up to the end of January 2001. Many spontaneous adverse event reports received since marketing, a third of these from non-healthcare professionals, reflect the underlying condition being treated. However, a number of events have resulted in changes to the zanamivir prescribing information, including rare reports of bronchospasm, dyspnoea, rash, urticaria and allergic type reactions including facial and oropharyngeal oedema. The reported safety profile of zanamivir, for treatment and prophylaxis of high risk subjects with influenza type A and B infections supports its continued use in these individuals who are likely to benefit most.

Reintroduction of influenza A to a nursing building.

We report an outbreak of influenza A from a four-building veterans' facility in King, Wisconsin. Influenza was isolated in 154 of 721 residents over a 121-day period. Building A had 2 cases, no isolates for 40 days, followed by 27 cases. Building B had 25 cases, no isolates for 75 days, followed by 4 cases. Building C had 23 cases, no isolates for 14 days, followed by 17 cases. Influenza A may be reintroduced to a nursing building. Surveillance with contingency plans for restarting of prophylaxis must continue for the duration of influenza in the community.

Clinical signs and symptoms predicting influenza infection.

BACKGROUND: New antiviral drugs are available for the treatment of influenza type A and type B infections. In clinical practice, antiviral use has rarely been guided by antecedent laboratory diagnosis. Defined clinical predictors of an influenza infection can help guide timely therapy and avoid unnecessary antibiotic use. OBJECTIVE: To examine which clinical signs and symptoms are most predictive of influenza infection in patients with influenza-like illness using a large data set derived from clinical trials of zanamivir. METHODS: This analysis is a retrospective, pooled analysis of baseline signs and symptoms from phase 2 and 3 clinical trial participants. It was conducted in mainly unvaccinated (mean age, 35 years) adults and adolescents who had influenza-like illness, defined as having fever or feverishness plus at least 2 of the following influenza-like symptoms: headache, myalgia, cough, or sore throat who underwent laboratory testing for influenza. Clinical signs and symptoms were evaluated in statistical models to identify those best predicting laboratory confirmation of influenza. RESULTS: Of 3744 subjects enrolled with baseline influenza-like symptoms, and included in this analysis, 2470 (66%) were confirmed to have influenza. Individuals with influenza were more likely to have cough (93% vs 80%), fever (68% vs 40%), cough and fever together (64% vs 33%), and/or nasal congestion (91% vs 81%) than those without influenza. The best multivariate predictors of influenza infections were cough and fever with a positive predictive value of 79% (P<. 001). The positive predictive value rose with the increase in the temperature at the time of recruitment. CONCLUSION: When influenza is circulating within the community, patients with an influenza-like illness who have both cough and fever within 48 hours of symptom onset are likely to have influenza and the administration of influenza antiviral therapy may be appropriate to consider. Arch Intern Med. 2000;160:3243-3247.

Immunization of healthy adults with a single recombinant pneumococcal surface protein A (PspA) variant stimulates broadly cross-reactive antibodies to heterologous PspA molecules.

Pneumococcal surface protein A (PspA) is a highly variable protein found on all strains of pneumococci. To be successful, a PspA-based vaccine for S. pneumoniae must induce antibodies that are broadly cross-reactive. To address whether cross-reactive antibodies could be induced in man, we evaluated serum from adults immunized with recombinant clade 2 PspA from strain Rx1. Immunization with 5-125 microg rPspA lead to a significant increase in circulating anti-PspA antibodies, as well as antibodies reactive to heterologous rPspA molecules. Increased binding of post-immune sera to 37 pneumococcal strains expressing a variety of PspA and capsule types was observed, versus pre-immune sera. The extent of cross-clade reactivity of human anti-rPspA followed roughly the amount of sequence homology to the non-clade 2 antigens. It is hypothesized that priming of humans by natural exposure to S. pneumoniae contributes to the breadth of the cross-reactivity of antibody to PspA.

The potential to use PspA and other pneumococcal proteins to elicit protection against pneumococcal infection.

Pneumococcal proteins, alone, in combination with each other, or in combination with capsular polysaccharide-protein conjugates may be useful pneumococcal vaccine components. Four proteins with a potential for use in vaccines are PspA, pneumolysin, PsaA, and PspC. In a mouse model of carriage, PsaA and PspC were the most efficacious vaccine proteins. Of these, PsaA was the best at eliciting protection against carriage. However, a combination of PspA and pneumolysin may elicit stronger immunity to pulmonary infection and possibly sepsis than either protein alone. Recently, a phase one trial of a recombinant family 1 PspA was completed in man. PspA was observed to be safe and immunogenic. Injection of 0.1 ml of immune serum diluted to 1/400 was able to protect mice from fatal infection with S. pneumoniae. Under these conditions, pre-immune serum was not protective. The immune human serum protected mice from infections with pneumococci expressing either of the major PspA families (1 and 2) and both of the pneumococcal capsular types tested: 3 and 6.

Surveillance for respiratory illness in long-term care settings: detection of illness using a prospective research technique.

BACKGROUND: The overall frequency and severity of viral respiratory infections affecting residents of long-term care facilities (LTCFs) is not well described. This is due primarily to the cumbersome and expensive techniques required for adequate surveillance of respiratory illnesses and the associated costs and availability of a laboratory capable of the relevant and timely report of diagnostic tests. Here we describe our technique for surveillance of respiratory illness in the LTCF. Elements of it may serve as strategies for routine care. METHODS: Nurses were trained to record respiratory complaints and to track them using a histogram-based calendar charting system. For the research technique, all new illnesses during the winter months, no matter how minor, were sampled for viral culture. RESULTS: Influenza A and B, parainfluenza types 1 through 4, herpes simplex virus types 1 and 2, rhinovirus, and respiratory syncytial virus (RSV) were detected in the nursing homes studied. Outbreaks of influenza were documented annually by prospective surveillance. Outbreaks of parainfluenza type 1 and RSV indistinguishable clinically from influenza were detected. CONCLUSIONS: Intense surveillance for respiratory illness and viral pathogens using the described research technique identified viral activity reliably on an annual basis in several large LTCFs. Elements of the research protocol may be adapted for general use to create a cost-effective surveillance program for LTCFs that have limited resources. Such a technique is essential for implementing effective measures for outbreak prevention and control.

Mortality following isolation of various respiratory viruses in nursing home residents.

OBJECTIVE: To compare mortality following isolation of influenza A to mortality following isolation of other respiratory viruses in a nursing home. SETTING: The Wisconsin Veterans Home, a 688-bed skilled nursing facility for veterans and their spouses. PARTICIPANTS: All residents with respiratory viral isolates obtained between 1988 and 1999. DESIGN: Thirty-day mortality was determined following each culture-proven illness. RESULTS: Thirty-day mortality following isolation of viral respiratory pathogens was 4.7% (15/322) for influenza A; 5.4% (7/129) for influenza B; 6.1% (3/49) for parainfluenza type 1; 0% (0/26) for parainfluenza types 2, 3, and 4; 0% (0/26) for respiratory syncytial virus (RSV); and 1.6% (1/61) for rhinovirus. CONCLUSIONS: Mortality following isolation of certain other respiratory viruses may be comparable to that following influenza A (although influenza A mortality might be higher without vaccination and antiviral agents). The use of uniform secretion precautions for all viral respiratory illness deserves consideration in nursing homes.

Zanamivir: a review of clinical safety.

Preclinical and clinical studies have clearly demonstrated that zanamivir, a potent and highly selective inhibitor of the influenza A and B virus neuraminidase, has an impressive safety profile. This report describes the safety and tolerability findings from the clinical studies completed up to the 17 July 1998 involving over 6000 adult and adolescent patients from North America, Europe and the Southern Hemisphere. Serious adverse events from an ongoing Japanese clinical programme are also reported. Zanamivir was administered in various dose forms and frequencies and was found to have a comparable safety profile with placebo when given for both the treatment and prophylaxis of influenza-like illness. These findings were independent of age and underlying medical condition. 4152 patients received zanamivir and the most commonly reported adverse events were consistent with the signs and symptoms of influenza-like illness. Most of the adverse events were mild and did not result in patient withdrawal from the studies. Less than 1% of zanamivir and placebo recipients reported a serious adverse event. In addition, 490 healthy volunteers received zanamivir in clinical pharmacology studies. It was well tolerated and the incidence of adverse events was similar in zanamivir and placebo recipients. In addition, no clinically significant laboratory abnormalities were detected. Results from in vitro and in vivo animal studies suggest that zanamivir has low acute toxicity and no significant systemic toxicity or respiratory tract irritancy at plasma exposures more than 100-fold higher than those anticipated following clinical use. Neither genotoxic nor reproductive types of toxicity have been observed in toxicology studies at doses equal to 17 to 197 times the current therapeutic dose (20 mg/day). The characteristics of the molecule and the low systemic exposure indicate a very low potential for drug interactions with the inhaled route. Furthermore, repeated 600mg intravenous doses were well tolerated in healthy volunteers. The observed safety profile of zanamivir compares favourably with currently available agents with anti-influenza virus activity, such as rimantadine and amantadine, as well as GS4104, a neuraminidase inhibitor currently in phase III development. This may be attributed to the low systemic bioavailability of zanamivir, which is given by oral inhalation, direct to the primary site of viral replication. The potential advantages of this include a reduced risk of drug-drug interactions, other nontarget organ toxicities (e.g. brain) and drug clearance issues from both kidney and liver. Therefore, the safety profile of zanamivir supports its use in the management of influenza.

Non-influenza respiratory viruses may overlap and obscure influenza activity.

OBJECTIVE: To report the number and timing of influenza A isolates, as well as overlapping respiratory viruses. Co-circulating respiratory viruses may obscure the determination of influenza activity. DESIGN: Prospective clinical surveillance for the new onset of respiratory illness followed by viral cultures during seven separate influenza seasons. SETTING: The Wisconsin Veterans Home, a skilled nursing facility for veterans and their spouses. RESULTS: Influenza A isolates were encountered in greater numbers than non-influenza A isolates during three seasons. Seasonal variability is striking. In December 1992, we identified a large outbreak of respiratory illness. Influenza type B was cultured from 102 residents. In December 1995, influenza A was cultured from 285 people in Wisconsin. At that time, we identified outbreaks of respiratory illness in two of our four buildings. Based on statewide data, we suspected an influenza outbreak; however, 26 isolates of parainfluenza virus type 1 were cultured with no influenza. The potential importance of culturing at the end of the season was demonstrated in 1991-1992 when an outbreak of respiratory syncytial virus (RSV) overlapped and extended beyond influenza A activity. CONCLUSIONS: When interpreting new clinical respiratory illnesses as a basis for declaring an outbreak of influenza A, clinicians should realize that co-circulating respiratory viruses can account for clinical illnesses. Clinicians might utilize healthcare dollars efficiently by performing cultures to focus the timing of influenza A chemoprophylaxis. Cultures could be performed when clinical outbreak criteria are approached to confirm an outbreak. Culturing of new respiratory illness could begin again before the anticipated discontinuation of prophylaxis (approximately 2 weeks).

Correlation of serum L-carnitine and dehydro-epiandrosterone sulphate levels with age and sex in healthy adults.

OBJECTIVES: L-carnitine and dehydro-epiandrosterone (DHEA) independently promote mitochondrial energy metabolism. We therefore wondered if an age-related deficiency of L-carnitine or DHEA may account for the declining energy metabolism associated with age. METHODS: we evaluated serum levels of L-carnitine and the sulphated derivative of DHEA (DHEAS) in cross-sectional study of 216 healthy adults, aged 20-95. RESULTS: serum DHEAS levels declined, while total carnitine levels increased with age (P < 0.0001). Total and free carnitine and DHEAS levels were lower in women than men (P < 0.0001). Esterified/free (E/F) carnitine (inversely related to carnitine availability) increased with age in both sexes (P=0.012). CONCLUSION: reduced carnitine availability correlates with the age-related decline of DHEAS levels. These results are consistent with the hypothesis that decreased energy metabolism with age relates to DHEAS levels and carnitine availability.

Carnitine and dehydroepiandrosterone sulfate induce protein synthesis in porcine primary osteoblast-like cells.

Age-related bone loss eventually leads to osteopenia in men and women. The etiology of age-related bone loss is currently unknown; however, decreased osteoblast activity contributes to this phenomenon. In turn, osteoblast proliferation and function is dependent on energy production, thus the loss of energy production that occurs with age may account for the deficient osteoblast activity. Carnitine and dehydroepiandrosterone-sulfate (DHEAS), both of which decline with age, promote energy production through fatty acid metabolism. Thus, we hypothesized that carnitine and DHEAS would increase osteoblast activity in vitro. Accordingly, we measured the effect of carnitine and DHEAS on palmitic acid oxidation as a measure of energy production, and alkaline phosphatase (ALP) activity and collagen type I (COL) as indices of osteoblast function in primary porcine osteoblast-like cell cultures. Carnitine (10(-3) and 10(-1) M) but not DHEAS (10(-9), 10(-8), and 10(-7) M) increased carnitine levels within the cells. Carnitine alone and in combination with DHEAS increased palmitic acid oxidation. Both carnitine and DHEAS alone and in an additive fashion increased ALP activity and COL levels. These results demonstrate that in osteoblast-like cells in vitro, energy production can be increased by carnitine and osteoblast protein production can be increased by both carnitine and DHEAS. These data suggest that carnitine and DHEAS supplementation in the elderly may stimulate osteoblast activity and decrease age-related bone loss.

Duration of antiviral prophylaxis during nursing home outbreaks of influenza A: a comparison of 2 protocols.

BACKGROUND: We performed a randomized trial of 2 protocols guiding the duration of antiviral chemoprophylaxis during outbreaks of influenza A in a rural, 700-bed nursing home for veterans and their spouses with 14 nursing units in 4 buildings. METHODS: Half of all residents volunteered to participate. Nursing units were randomized, and the effectiveness of short-term (minimum, 14 days and 7 days without the onset of a case in the building) vs long-term (minimum, 21 days and 7 days without the onset of a case in the 4-building facility) prophylaxis was compared using amantadine hydrochloride in the influenza seasons of 1991-1992 and 1993-1994 and rimantadine hydrochloride in the influenza season of 1994-1995. A "case" is defined as an incident of a respiratory tract illness and the isolation of an influenza virus organism. We compared the number of cases after the discontinuation of short- vs long-term chemoprophylaxis. Prospective surveillance identified residents with new respiratory tract symptoms, and specimens for viral cultures were obtained even in the absence of temperature elevation. RESULTS: We documented influenza A virus activity during 3 seasons (32, 68, and 12 patients, respectively). During the 1991-1992, 1993-1994, and 1994-1995 influenza seasons, the patients on 11 floors were assigned to receive short-term chemoprophylaxis and those on 10 floors were assigned to long-term chemoprophylaxis. Only in 1993-1994 did chemoprophylaxis extend beyond 14 or 21 days when new cases continued beyond 14 days. Amantadine-resistant strains were circulating at that time. None of the participants in the prospective, controlled study had influenza develop after the termination of short- or long-term chemoprophylaxis. CONCLUSION: Antiviral chemoprophylaxis can be administered for the longer duration of 14 days or, in the absence of new culture-confirmed illness in the nursing building, for 7 days.

Assessment of markers of the cell-mediated immune response after influenza virus infection in frail older adults.

The purpose of this study was to determine whether measures of the cell-mediated immune response to influenza virus could be used as markers of influenza virus infection. We studied 23 subjects who developed upper respiratory, lower respiratory, or systemic symptoms during a small outbreak of influenza in a nursing home population. Influenza virus culture from nasopharyngeal swabs yielded influenza virus isolates from 7 of the 23 subjects. Only three of the subjects had a fourfold rise in antibody titer to the influenza virus antigen positivity after the infection. Granzyme B and cytokine levels were measured in peripheral blood mononuclear cells (PBMC) obtained from all subjects and stimulated with live influenza virus. Elevated granzyme B levels in virus-stimulated PBMC in combination with lower respiratory tract or systemic symptoms in study subjects was a significant predictor of culture-confirmed influenza virus infection compared to those from whom influenza virus could not be identified. Cytokine levels did not distinguish between the two groups in a similar type of analysis. Granzyme B in combination with the clinical profile of symptoms may be a useful retrospective marker for influenza virus infection.

Efficacy of zanamivir for chemoprophylaxis of nursing home influenza outbreaks.

Despite vaccination, influenza remains a common of morbidity in nursing homes. Chemoprophylaxis of residents with currently available antivirals is not always effective and new agents effective against both influenza A and B are needed. In a randomized, unblinded pilot study, we compared 14 day chemoprophylaxis with zanamivir, an antiviral which inhibits influenza neuraminidase, to standard of care during sequential influenza A and influenza B outbreaks in a 735 bed nursing home. Influenza A outbreaks were declared on 6/14 epidemic units. Sixty-five volunteers on four epidemic units were randomized to zanamivir and on two epidemic units, 23 volunteers were randomized to rimantadine. During the 14 days of prophylaxis, only four new febrile respiratory illnesses were detected. One volunteer receiving rimantadine prophylaxis developed laboratory-confirmed influenza. Influenza B outbreaks were declared on 3/14 epidemic units. Thirty-five volunteers on two epidemic units were randomized to zanamivir and 18 volunteers on one epidemic unit were randomized to no drug. During the 14 days of prophylaxis, only one new febrile respiratory illness was detected. One volunteer randomized to receive no drug developed laboratory-confirmed influenza. Zanamivir appears comparably effective to standard of care in preventing influenza-like illness and laboratory-confirmed influenza in nursing homes, but requires further testing.

Evaluation of the safety and immunogenicity of a new, heat-treated human rabies immune globulin using a sham, post-exposure prophylaxis of rabies.

A double-blind, controlled, randomized trial was conducted to evaluate the safety and immunogenicity of a new human rabies immune globulin (HTRIG). This product, manufactured by Pasteur Merieux Connaught, PMC, has undergone a heat-treatment step (10 h at 60 degrees C) and removal of mercurothiolate. The corresponding unheated product available from the same manufacturer (human rabies immune globulin, HRIG, IMOGAM RABIES[spr2]) was used for comparison. These two rabies immune globulins (RIGs) were administered either alone or in association with the human diploid cell rabies vaccine (HDCV, IMOVAX[spr2] RABIES, PMC) according to a standard, post-exposure rabies prophylaxis schedule. Sixty-four healthy adults were randomly assigned to four groups of 16 to receive either HRIG/placebo, HTRIG/placebo, HRIG/HDCV or HTRIG/HDCV. RIG was administered at the recommended dose of 20 IU/kg by three intramuscular (i.m.) injections in the gluteus. HDCV or placebo was given on day (D) 0, D3, D7, D14, and D28 into the deltoid by the intramuscular (i.m.) route. Any local reaction from D0 to D3 at the immune globulin injection site, and any systemic reaction from D0 to D42, were monitored by subject diaries. Rabies-neutralizing serum antibody levels were assessed by the rapid fluorescent focus inhibition test (RFFIT) before treatment and on D3, D7, D14, D28, D35, and D42. No serious adverse reactions and, in particular, no allergic-type reactions were reported. The safety profiles of HTRIG and HRIG were similar, except that complaints of pain, or tenderness at the injection site were half as common in the HTRIG group. Most of the local reactions were mild or moderate. After the administration of HTRIG/placebo or HRIG/placebo, 60% of subjects had detectable rabies antibodies levels, but by D42 all titres were below the seroprotective level (i.e. below 0.5 IU/ml). In the groups HTRIG/HDCV and HRIG/HDCV, the antibody titres rose markedly from D7, and reached a maximum value of 19 IU/ml (95% CI, 11 to 38 IU/ml) and 31 IU/ml (95% CI, 20 to 48 IU/ml), respectively, on day 14. All subjects who received RIG and vaccine maintained a protective antibody level from D14 to D42. No significant difference in immunogenicity results between these two groups (HTRIG/HDCV and HRIG/HDCV) was observed, and no interference of immune globulin with vaccine was reported. The safety and immunogenicity profiles of PMC HTRIG appear comparable with the current reference product. The heat-treatment step will enhance the safety by further reducing the probability of virus transmission through immune globulin treatment. The low levels of rabies antibodies obtained by intramuscular administration of either PMC HTRIG or of PMC HRIG support the recommendations that call for local infiltration of wounds with RIG.