Animal experiments show impact of vaccination on reduction of SARS-CoV-2 virus circulation: A model for vaccine development?

BACKGROUND: In the pre-clinical phase, SARS-CoV-2 vaccines were tested in animal models, including exposure trials, to investigate protection against SARS-CoV-2. These studies paved the way for clinical development. The objective of our review was to provide an overview of published animal exposure results, focussing on the capacity of vaccines to reduce/prevent viral shedding. METHOD: Using Medline, we retrieved eighteen papers on eight different vaccine platforms in four animal models. Data were extracted on presence/absence of viral RNA in nose, throat, or lungs, and neutralizing antibody levels in the blood. RESULTS: All vaccines showed a tendency of reduced viral load after exposure. Particularly nasal swab results are likely to give an indication about the impact on virus excretion in the environment. Similarly, the reduction or prevention of viral replication in the bronchoalveolar environment might be related with disease prevention, explaining the high efficacy in clinical trials. DISCUSSION: Although it remains difficult to compare the results directly, the potential for a strong reduction of transmission was shown, indicating that the animal models predicted what is observed in the field after large scale human vaccination. This merits further attention for standardization of exposure experiments, with the intention to speed up future vaccine development.

Where are we in our understanding of the association between narcolepsy and one of the 2009 adjuvanted influenza A (H1N1) vaccines?

Evaluating new rare serious vaccine safety signals is difficult and complex work. To further assess the observed increase in narcolepsy cases seen in Europe with the 2009 pandemic H1N1 influenza vaccine, the International Alliance for Biological Standardization (IABS) invited a wide range of experts to a one day meeting in Geneva in October 2015 to present data and to discuss the implications. The presentations covered the following topics: clinical picture of childhood narcolepsy following the 2009 H1N1 pandemic vaccination campaigns; epidemiological studies conducted to assess the risk of narcolepsy, other neurological and immune-related diseases following 2009 pandemic H1N1 influenza vaccine; potential biases influencing the different epidemiological study designs; potential genetic contribution to the development of narcolepsy; potential biological mechanisms for development of narcolepsy in this setting including the role of the virus itself, antigenic differences between the vaccines and differences in AS03-adjuvanted vaccines. The presentations were followed by fulsome roundtable discussions. Members from affected families also attended and made informal comments to round out the day's deliberations. This meeting emphasized the value added in bringing together in a neutral setting a wide range of experts and vaccine producers to discuss such a complex new serious adverse event following immunization.

Cohesive Polydensified Matrix® cross-linked hyaluronic acid volumizing gel: a magnetic resonance imaging and computed tomography study.

BACKGROUND: Concentrated hyaluronic acid (HA) gels with a high degree of cross-linking such as Cohesive Polydensified Matrix® (CPM) HA have been designed for long-term facial volume restoration. OBJECTIVE: To determine the behavior and longevity of CPM HA gel, a case series of subjects underwent magnetic resonance imaging (MRI) or computed tomography (CT) scans several years after their initial treatment. METHODS: Six subjects, three from the initial CPM HA Conformité Européenne registration study and three from private practice who had received prior injection of CPM HA for facial volumizing indications agreed to undergo an MRI or CT scan at intervals ranging from 1 to 4 years after the initial treatment. The amount of HA gel originally injected was compared with the amount estimated from volumetric analysis of the MRI and CT scans. The scans were also examined for the signs of any abscess or granuloma formation and to determine the behavior of the HA gel over time. RESULTS: CT and MRI imaging of the six study subjects indicated CPM HA gel persisted for 2-4 years after only a single treatment. In some patients, product was evident in deeper facial fat compartments than originally injected suggesting some diffusion of product had occurred. There was no MRI or CT evidence of abscess or granuloma formation. CONCLUSION: Our findings indicate that CPM HA volumizing gel has substantial longevity when injected subcutaneously or in deep soft tissues.

Inhibition of virus replication in the tonsils of pigs previously vaccinated with a Chinese strain vaccine and challenged oronasally with a virulent strain of classical swine fever virus.

After an oronasal (O.N.) infection with classical swine fever (C.S.F.) virus, virus multiplication can be detected in the tonsils from Day 2 post infection (p.i.) till death. The course of viral replication during the first 10 days after O.N. challenge exposure of pigs, previously vaccinated with a Chinese strain vaccine in the presence or absence of maternal antibodies, was studied using direct immunofluorescence techniques on cryostat sections and virus isolations. When piglets were challenged O.N. in the presence of maternal antibodies, virus replication in the tonsils still occurred. The multiplication period and the localization of the virus, however, were directly correlated to the maternal antibody levels. The maternal antibody level also seems responsible for the efficacy of the vaccination to prevent challenge virus replication in the tonsils: vaccination in the presence of low maternal antibody titers completely inhibited virus replication; vaccination in the presence of high maternal antibody titers only reduced the multiplication period of the O.N.-administered virulent virus. In both cases, animals were challenged 1 week post vaccination. Vaccination of seronegative animals resulted in an almost complete inhibition of the virus replication in the tonsils during a full fattening period: cryostat sections revealed a limited virus replication in three out of 20 animals. In one of these animals, virus replication was probably so negligible that virus isolation remained negative.

Oronasal challenge of fattening pigs after vaccination with an inactivated Aujeszky's disease vaccine.

Groups of pigs from vaccinated and unvaccinated sows were vaccinated once or twice between the ages of eight and 20 weeks with a commercial inactivated, oil adjuvanted Aujeszky's disease virus vaccine. Pigs were challenged by the oronasal route when 22 to 27 weeks old. Pigs from unvaccinated sows developed neutralising antibodies after vaccination but no seroconversion was detected in eight-week-old pigs or in 80 per cent of 15-week-old pigs from vaccinated sows. Challenge resulted in severe disease and weight loss in control pigs. In vaccinated animals the duration and severity of clinical signs and the amount of weight lost decreased with increasing serum neutralisation titres. The results indicate that parenteral vaccination at weaning with the vaccine described will not protect pigs at slaughter age against infection and disease, particularly if they were born from seropositive mothers.

Classical swine fever: the European experience and a guide for infected areas.

Classical swine fever (CSF) (hog cholera) virus infection is still of world-wide concern, either because of the direct effects of the disease on swine breeding in areas where the virus is epizootic or enzootic, or as a threat in areas where the virus has been eradicated. The authors provide an overview of the characteristics of the disease. Special emphasis is placed on the chronic form of disease, particularly in the late stages of eradication programmes. In the early 1980s, the European Union (EU) was composed of countries which were officially free of the disease (absence of infection and no vaccination) and countries in which vaccination was either permitted or was compulsory. To ensure free trade between the Member States, an eradication plan was agreed upon and implemented. Initially, the plan consisted of a combination of vaccination with the Chinese strain of the virus and slaughter and removal of infected herds. Consequently, when the number of infected herds was low, vaccination was abandoned and the control of CSF was conducted exclusively by eradication (removal and slaughter). The United Kingdom, Austria, Denmark, Ireland, Luxembourg, Finland and Sweden ceased vaccination before 1980. In the other countries, vaccination was useful in controlling the last epidemics and was finally ceased as follows: France in 1983, the Netherlands in 1986, Belgium, Spain and Greece in 1988, Germany in 1989 and Italy in 1990. From 1990 onwards, no vaccination against CSF has been performed in the EU. New techniques for the diagnosis of CSF (for example, the enzyme-linked immunosorbent assay based on the detection of the p125 antigen of the virus) have been shown to be of value in the early detection of infected animals. In enzootic areas, the use of vaccines based on the Chinese strain has been successful. Vaccines with at least 100 PD50 of virus per dose are able to significantly limit the replication of virulent virus in the tonsils. Consequently, shedding of virus after infection can be reduced considerably. In heavily infected areas, vaccination plays a crucial role. The European experience shows that eradication may be achieved when vaccination with highly effective vaccines is combined with effective identification of swine, movement control, early diagnosis and the rapid elimination of infected herds.

Effect of experimental infection with pseudorabies (Aujeszky's disease) virus on pigs with maternal immunity from vaccinated sows.

Live-virus and inactivated-virus vaccines were used to immunize sows against pseudorabies (Aujeszky's disease) virus. To test the efficacy of the vaccination, 53 pigs of different ages were taken from the 1st and the 2nd litters of vaccinated sows and placed separately in isolation units. The pigs were challenge exposed with virulent pseudorabies virus and examined for clinical signs, virus excretion, and serologic reaction. The challenge inoculum caused severe nervous or respiratory signs of disease in 12 of the 13 control pigs, with a mortality of 76%. The pigs from the 1st litters of sows vaccinated with the live-virus vaccine did not become sick, whereas 2 of the 9 pigs (22%) from the 2nd litters had clinical signs and died of pseudorabies. All pigs from sows vaccinated with the inactivated-virus vaccine remained healthy. The results of virus isolation from oronasal swabs, combined with the serotest results, indicated that challenge exposure of all except 1 of the pigs resulted in a subclinical infection with the formation of active immunity.

Vaccination of cattle against pseudorabies (Aujeszky's disease) with homologous virus (herpes suis) and heterologous virus (herpes bovis 1).

Study was made to determine whether vaccination of cattle against pseudorabies (PR; Aujeszky's disease) affords protection upon subsequent intranasal challenge exposure with virulent virus. Vaccinations were performed with a commercially available oil-adjuvant PR virus vaccine, in some cases supplemented with A1(OH)3 (given subcutaneously), with the attenuated NIA4 strain of PR virus (given intranasally), and with a commercially available temperature-sensitive mutant of bovine herpesvirus-1 (infectious bovine rhinotracheitis [IBR] virus) given intranasally. Challenge exposure was performed intranasally with 10(3) median lethal doses (LD50) of the virulent PR virus. In earlier experiments, it was found that LD50 median tissue culture infective doses of this virulent PR virus in primary pig kidney cells represented about 1 LD50 for cattle. This LD50 was practically no different for cattle whether or not they had antibodies against PR virus before exposure to virulent PR virus. In the seropositive animals, antibodies were present presumably as a consequence of a previous IBR infection in the field. Vaccination intranasally with NIA4 or IBR virus did not result in serologic response or protection against challenge exposure. The inactivated-virus vaccine induced a good serologic reaction, but there was poor protection against challenge exposure. Consequently, vaccination of cattle at risk of exposure to virulent PR virus cannot be advised. In the present experiments, initiation of infection with virulent PR virus in cattle always resulted in disease and death.

Adsorption of colostral antibodies against classical swine fever, persistence of maternal antibodies, and effect on response to vaccination in baby pigs.

OBJECTIVE: To determine kinetics of antibody absorption, persistence of antibody concentrations, and influence of titers on vaccination of baby pigs with a vaccine against classical swine fever (CSF). ANIMALS: 15 sows and their litters. PROCEDURE: Farrowings were supervised. Initial time of suckling was recorded. In the first experiment, blood samples were collected at farrowing, 2 and 4 hours after suckling, and hourly until 10 hours after initial suckling. Samples were assayed for CSF antibodies, using a serum neutralizing (SN) test. A second experiment included 33 baby pigs vaccinated as follows: 10 prior to ingestion of colostrum, 18 between 1 and 4 hours after ingestion of colostrum, and 5 at 12 hours after ingestion of colostrum. Fourteen pigs were vaccinated when 7 weeks old, and 15 pigs were not vaccinated. At 10 weeks of age, pigs were challenge-exposed with virulent CSF virus. Blood samples were collected and assayed for CSF antibodies and p125 antigen and p125 antibodies. RESULTS: CSF antibodies were detected in pigs beginning 2 hours after suckling. Colostral antibodies persisted for > 7 weeks (half-life, 79 days). Vaccination of pigs before suckling provided effective protection from severe disease after challenge-exposure. However, vaccination of neonates with antibody titers was not effective, because 19 of 23 (82%) pigs succumbed after challenge-exposure. All pigs vaccinated when 7 weeks old resisted challenge-exposure, whereas all unvaccinated control pigs succumbed. CONCLUSIONS AND CLINICAL RELEVANCE: Vaccination before ingestion of colostrum conferred good protection against CSF in baby pigs. Vaccination of 7-week-old pigs that had decreasing concentrations of passively acquired antibodies was efficacious.

Vaccination against pseudorabies with glycoprotein gI+ or glycoprotein gI- vaccine.

Subunit pseudorabies vaccines that contained only purified glycoproteins of either of 2 strains of pseudorabies virus (PRV) were prepared and subsequently tested for safety and efficacy. The strains of virus used for vaccine production differed in at least 2 properties. One strain (Kojnok) was virulent for pigs and was believed to code for the entire complement of viral glycoproteins. The other (Kaplan) was a deletion mutant that was unable to code for structural viral glycoproteins gI and gp63. Purified glycoproteins were dispersed in an oil-in-water emulsion and were administered IM to pigs. Both vaccines were found to be safe and effective immunogens. Neither caused any local or general reactions, as verified by examination of the injection site (local safety) and by vaccination of pregnant sows in PRV-infected and noninfected herds. Sows vaccinated with the gI+ or gI- vaccine protected their pigs at levels of 93 and 92%, respectively, against a severe challenge exposure that killed 98% of pigs born from nonvaccinated sows. Vaccinated pigs were tested for active immunity by intranasal challenge exposure with the NIA 3 strain. Protection was quantitated by measuring the relative daily weight difference, expressed in percent per day, between vaccinated and control pigs during the first week after challenge exposure (delta G7); the estimated differences were 2.25 and 2.13% for gI+ and gI- vaccines, respectively. The absence of gI and gp63 did not affect the efficacy of this type of subunit glycoprotein vaccines.(ABSTRACT TRUNCATED AT 250 WORDS)

Skin test as herd diagnosis for Aujeszky's disease (Pseudorabies) in swine.

Summary The value of a skin test for the diagnosis of Aujeszky's disease (pseudorabies) in swine was examined. Semipurified and concentrated antigens, obtained by ether/tween 80 inactivation of Aujeszky's disease virus, were inoculated intradermally into seronegative, experimentally infected and vaccinated swine and into pigs with maternal antibodies. A specific skin reaction, characterized by a visible indurated swelling, was observed within 24 hours in animals with active immunity, No reaction was seen in pigs with maternal immunity or in seronegative uninfected and unvaccinated animals. In the infected and vaccinated groups, 89% and 58% respectively of the animals with seroneutralizing antibodies were positive by the skin test response. Positive reactions were observed as early as 8 days after the infection. All but one seronegative animals remained free of antibodies after 2 consecutive skin tests and the course of decline of maternal antibodies was not changed. An earlier skin test did not lead to sensitization for a later application. The present results, together with field experience on 8 farms, revealed that the skin test could be considered a reliable method for diagnosis of Aujeszky's disease in swine on a herd basis.

[Hip fractures in the elderly; mortality, functional results and probability of returning home]. / Heupfracturen bij bejaarden; sterfte, functionele resultaten en kans op huiswaarts keren.

767 patients over the age of 70 with a fracture of one hip were studied prospectively. The results were compared with the literature. The overall mortality rate within 3 months was 24%. This mortality was significantly influenced by the general health condition of the patient at the time of the injury, his living quarters and the ability to walk again after operation (p less than 0.001). For 38% of the survivors, able-bodied before the injury, the fracture meant an important loss of functional independence. The degree of impairment was closely related to the patient's age and fracture type (p less than 0.05). Of patients living in their own homes before injury only 60% were able to go back home. In predicting the probability of going back home, the functional status before injury and the ability to walk again at the time of discharge from the surgical department were highly important (p less than 0.001).

Missed posterior fracture dislocation of the shoulder. Closed reduction and pinning.

In four missed posterior shoulder dislocations, a trial of closed reduction was successful, but severe instability required further therapy. The glenohumeral joints were immobilized by 3 to 4 percutaneously inserted threaded pins. Removal of the pins after 4 to 6 weeks was followed by physiotherapy. After a follow-up of 4 to 42 months, the functional results of this simple procedure are good and there is no recurrence. Bending of the ends of the pins, a very careful follow-up to deal with pin migration, and adequate prevention of subsequent convulsions in epileptic patients are mandatory.

Skin test as herd diagnosis for Aujeszky's disease (pseudorabies) in swine.

The value of a skin test for the diagnosis of Aujeszky's disease (pseudorabies) in swine was examined. Semipurified and concentrated antigens, obtained by ether/tween 80 inactivation of Aujeszky's disease virus, were inoculated intradermally into seronegative, experimentally infected and vaccinated swine and into pigs with maternal antibodies. A specific skin reaction, characterized by a visible indurated swelling, was observed within 24 hours in animals with active immunity. No reaction was seen in pigs with maternal immunity or in seronegative uninfected and unvaccinated animals. In the infected and vaccinated groups, 89% and 58% respectively of the animals with seroneutralizing antibodies were positive by the skin test response. Positive reactions were observed as early as 8 days after the infection. All but one seronegative animals remained free of antibodies after 2 consecutive skin tests and the course of decline of maternal antibodies was not changed. An earlier skin test did not lead to sensitization for a later application. The present results, together with field experience on 8 farms, revealed that the skin test could be considered a reliable method for diagnosis of Aujeszky's disease in swine on a herd basis.

Influence of planar cracks in plates on reflected and transmitted fields of Gaussian acoustic beams.

The scattering of a Gaussian beam by a rectangular crack is studied by means of the radiation mode model. The orthogonal set of modes for a L/S/V structure is derived, and a general mode decomposition formula is developed. The influence of a crack on the reflected and transmitted fields of a bounded beam, incident at critical angles of the L/S/L- and the L/S/V structure, is studied and physical interpretations are given. From those interpretations, the starting point of the crack is deduced along with the length and distance to the surface. Effects on focused beams are considered as well.

Extension of the mode method for viscoelastic media and focused ultrasonic beams.

In the present study viscoelasticity is introduced in the mode model and the orthogonality condition is adapted for viscous media. The expansion of convergent acoustic Gaussian beams in terms of radiation modes for viscoelastic media is studied as well. The effects on the reflected and transmitted profiles of acoustic beams incident from an ideal liquid onto a viscoelastic plate are shown and physically explained. It is shown that focusing the incident beam can suppress divergence effects and gives the possibility to measure shear wave attenuation coefficients.

Evidence for the natural transmission of influenza A virus from wild ducts to swine and its potential importance for man.

In 1979, epidemics of influenza occurred in pigs in Belgium from which were isolated strains of influenza A (Hsw1N1) virus antigenically closely related to Hsw1N1 strains previously isolated from ducks in North America and the Federal Republic of Germany. This finding is considered as the first supportive evidence that an influenza A virus in an avian species might have been transmitted to mammals.