Prostate-Specific Membrane Antigen-Targeted Therapy in Prostate Cancer: History, Combination Therapies, Trials, and Future Perspective.

In the last decades, the development of PET/CT radiopharmaceuticals, targeting the Prostate-Specific Membrane Antigen (PSMA), changed the management of prostate cancer (PCa) patients thanks to its higher diagnostic accuracy in comparison with conventional imaging both in staging and in recurrence. Alongside molecular imaging, PSMA was studied as a therapeutic agent targeted with various isotopes. In 2021, results from the VISION trial led to the Food and Drug Administration (FDA) approval of [177Lu]Lu-PSMA-617 as a novel therapy for metastatic castration-resistant prostate cancer (mCRPC) and set the basis for a radical change in the future perspectives of PCa treatment and the history of Nuclear Medicine. Despite these promising results, primary resistance in patients treated with single-agent [177Lu]Lu-PSMA-617 remains a real issue. Emerging trials are investigating the use of [177Lu]Lu-PSMA-617 in combination with other PCa therapies in order to cover the multiple oncologic resistance pathways and to overcome tumor heterogeneity. In this review, our aim is to retrace the history of PSMA-targeted therapy from the first preclinical studies to its future applications in PCa.

A Systematic Review on Organ-on-a-Chip in PDMS or Hydrogel in Dentistry: An Update of the Literature.

Organs-on-a-chip (OoCs) are microfluidic devices constituted by PDMS or hydrogel in which different layers of cells are separated by a semipermeable membrane. This technology can set many parameters, like fluid shear stress, chemical concentration gradient, tissue-organ interface, and cell interaction. The use of these devices in medical research permits the investigation of cell patterning, tissue-material interface, and organ-organ interaction, mimicking the complex structures and microenvironment of human and animal bodies. This technology allows us to reconstitute in vitro complex conditions that recapitulate in vivo environments. One of the main advantages of these systems is that they represent a very realistic model that, in many cases, can replace animal experimentation, eliminating costs and related ethical issues. Organ-on-a-chip can also contain bacteria or cancer cells. This technology could be beneficial in dentistry for testing novel antibacterial substances and biomaterials, performing studies on inflammatory disease, or planning preclinical studies. A significant number of publications and reviews have been published on this topic. Still, to our knowledge, they mainly focus on the materials used for fabrication and the different patterns of the chip applied to the experimentations. This review presents the most recent applications of organ-on-a-chip models in dentistry, starting from the reconstituted dental tissues to their clinical applications and future perspectives.

Alveolar Ridge Preservation Procedures Performed with a Freeze-Dried Bone Allograft: Clinical and Histologic Outcomes in a Case Series: Part II

INTRODUCTION: Tooth extractions can result in alveolar bone dimensional changes, necessitating additional bone grafting for implant placement. Alveolar Ridge Preservation (ARP) aims to counteract post-extraction changes. This study evaluates the bone regenerative properties of a freeze-dried bone allograft (FDBA) and the clinical outcomes of implants in grafted extraction sites. MATERIALS AND METHODS: This case series enrolled 33 patients undergoing single/multiple tooth extractions followed by ARP. Biopsies were harvested during implant placement for histologic and histomorphometric analysis. Clinical outcomes included marginal bone loss and Pink Esthetic Score (PES). RESULTS: 25 patients completed the study. FDBA augmented sockets exhibited new bone formation adjacent to graft particles. Implants (n=25) showed 100% survival and success rates at 1 and 2 years. PES improved significantly over time (p<.001), while marginal bone loss did not significantly differ at 1 and 2 years (p=.096). Specimens showed trabecular bone, residual FDBA particles, and marrow spaces. High magnification revealed immature bone and woven bone bridges around graft particles. No inflammatory cells were observed. CONCLUSIONS: The case series provides valuable insights into ARP performed with FDBA; implants were placed after 3 months of healing without any additional bone augmentation, the histologic outcomes were favorable, and implants were successful after a 2-year period of follow-up.

Resonance Frequency Analysis to Assess the Stability of Immediate Implants: A Retrospective Clinical Trial.

Adequate implant primary stability is a key factor to obtain osseointegration and can be measured at insertion by insertion torque (IT) and at different timepoints with resonance frequency analysis (RFA), expressed as an implant stability quotient (ISQ). This retrospective study investigated the correlation between ISQ and IT at implant insertion. All patients who were eligible for this single-cohort retrospective clinical trial were treated with an immediate implant. IT parameters were recorded at implant insertion, and ISQ values were recorded at insertion and at 2-, 4-, and 12-month follow-ups. The study comprised 23 patients who received 32 implants. The mean IT value was 46.87 ± 9.66 Ncm (range: 25 to 65 Ncm), and the mean ISQ value at implant insertion was 71.45 ± 4.24 (range: 63 to 78); these values showed a statistically significant correlation (P < .0001). According to the present data and considering the implant design used in this trial, there is a statistically significant and positive correlation between IT and ISQ values. Thus, ISQ can be used as a reliable method to measure implant stability over time.

Photodynamic Therapy with Aminolevulinic Acid Enhances the Cellular Activity of Cells Cultured on Porcine Acellular Dermal Matrix Membranes Used in Periodontology.

This study aims to test a photodynamic protocol based on a gel containing aminolevulinic acid followed by red-LED (ALAD-PDT) irradiation on human gingival fibroblasts (hGFs) and osteoblasts (hOBs) cultured on a porcine acellular dermal matrix membrane (PADMM). In the previous literature, ALAD-PDT showed solid antibacterial activity and proliferative induction on HGFs cultured on plates and HOBs cultured on a cortical lamina. PADMMs are used in dentistry and periodontology to treat gingival recessions and to increase the tissue thickness in the case of a thin biotype without the risks or postoperative discomfort associated with connective tissue grafts. However, one of the possible complications in this type of surgery is represented by bacterial invasion and membrane exposition during the healing period. We hypothesized that the addition of ALAD-PDT to PADMMs could enhance more rapid healing and decrease the risks connected with bacterial invasion. In periodontal surgery, PADMMs are inserted after a full-thickness flap elevation between the bone and the flap. Consequently, all procedures were performed in parallel on hOBs and hGFs obtained by dental patients. The group control (CTRL) was represented by the unexposed cells cultured on the membranes, group LED (PDT) were the cells subjected to 7 min of red LED irradiation, and ALAD-PDT were the cells subjected to 45 min of ALAD incubation and then to 7 min of red LED irradiation. After treatments, all groups were analyzed for MTT assay and subjected to histological examination at 3 and 7 days and to the SEM observations at 3, 7, and 14 days. Different bone mineralization assays were performed to quantify the effects of ALAD-PDT on hOBs: ALP activity, ALP gene expression, osteocalcin, and alizarin red. The effects of ALAD-PDT on hGFs were evaluated by quantifying collagen 1, fibronectin, and MMP-8. Results showed that ALAD-PDT promoted cellular induction, forming a dense cellular network on hOBs and hGFs, and the assays performed showed statistically significantly higher values for ALAD-PDT with respect to LED alone and CTRLs. In conclusion, ALAD-PDT could represent a promising aid for enhancing the healing of gingival tissues after PADMM applications.

Effect of alveolar ridge preservation on peri-implant mucositis and peri-implantitis prevalence: A multicenter, cross-sectional study.

OBJECTIVES: Alveolar ridge preservation (ARP) is a procedure with the aim to reduce bone resorption that occurs after tooth extraction, facilitating the following implant placement. The aim of this cross-sectional study was to evaluate the prevalence of mucositis and peri-implantitis around implants inserted in sites treated with ARP and to investigate possible risk factors. MATERIALS AND METHODS: Patients who received at least one dental implant inserted in a grafted socket were considered eligible for this study. Patients were recalled for a follow-up visit; medical history, clinical and demographic data were collected. Univariate logistic regression analyses have been performed for both implant-level and patient-level variables. Indeed, moderation analysis was used to investigate the indirect relationship between age and marginal bone level. RESULTS: Fifty-one patients who received 61 implants were enrolled in this cross-sectional study. Thirty-three implants were classified as "healthy" (54.1%), 23 implants showed signs of peri-implant mucositis (37.7%), and 5 implants were diagnosed with peri-implantitis (8.2%). Data analyzed at the patient level showed that 49% of the patients were healthy, 45.1% of the patients had mucositis and 5.9% of the patients were affected by peri-implantitis. Mandibular sites and type III grafted sockets showed a significant association with peri-implantitis; in addition, a history of periodontitis and an increase in age showed higher risks of developing mucositis or peri-implantitis. CONCLUSIONS: Implants inserted in grafted sockets showed favorable rates of healthy implants in the long term. CLINICAL RELEVANCE: The ridge preservation procedures do not seem to increase the risk of developing mucositis or peri-implantitis.

The Use of Zirconia for Implant-Supported Fixed Complete Dental Prostheses: A Narrative Review.

The success of implant-supported fixed complete dental prostheses (ISFCDPs) depends on multiple factors: some are related to the fixtures, such as fixture material, surface characteristics, positioning, and type of connection to prosthetic components; others are related to the prostheses, such as design and materials used. Zirconia is a material widely used in fixed prosthodontics, whether on natural teeth or on implants, with excellent results over time. Regarding the use of zirconia for ISFCDPs, the 2018 ITI Consensus Report stated that "implant-supported monolithic zirconia prostheses may be a future option with more supporting evidence". Since CAD/CAM technology and zirconia are being continuously innovated to achieve better results and performances over time, a narrative review of the literature seems necessary to focus research efforts towards effective and durable solutions for implant-supported, full-arch rehabilitations. The objective of the present narrative review was to search the literature for studies regarding the clinical performance of zirconia-based ISFCDPs. According to the results of this review, the use of zirconia for ISFCDPs showed good clinical outcomes, with high survival rates ranging from 88% to 100% and prosthetic complications that were restorable by the clinicians in most cases.

Alveolar Ridge Preservation Procedures Performed with a Freeze-Dried Bone Allograft: Histologic Outcomes in a Cohort Study.

The primary aim of this study was to assess the histomorphometric outcomes of extraction sockets grafted with freeze-dried bone allograft (FDBA) and sealed with a collagen membrane after 3 months of healing in specific region of interest (ROI) areas. The secondary aims were to analyze the biomaterial resorption rate, the bone-to-biomaterial contact (BBC), and the area and perimeter of grafted particles compared with commercially available FDBA particles. Fifteen patients underwent tooth extractions and ridge preservation procedures performed with FDBA and a collagen membrane. Bone biopsy samples were harvested after 3 months at the time of implant placement for histologic and histomorphometric analysis. Two areas of concern (ROI1 and ROI2) with different histologic features were identified within the biopsy samples; ROI1, ROI2, and commercially available particles were analyzed and compared. The following parameters were analyzed: newly formed bone, marrow space, residual graft particles, perimeter and area of FDBA particles, and BBC. The histomorphometric analysis showed 35.22% ± 10.79% newly formed bone, 52.55% ± 16.06% marrow spaces, and 12.41% ± 7.87% residual graft particles. Moreover, the histologic data from ROI1 and ROI2 showed that (1) the mean percentage of BBC was 64.61% ± 27.14%; (2) the newly formed bone was significantly higher in ROI1 than in ROI2; (3) the marrow space was significantly lower in ROI1 than in ROI2; and (4) the FDBA particles in ROI1 sites showed significantly lower area and perimeter when compared to commercially available FDBA particles. This latter data led to the hypothesis that FDBA particles embedded in newly formed bone undergo a resorption/remodeling process.

Functionalization of a Cortical Membrane with a Photodynamic Protocol.

Guided bone regeneration (GBR) comprehends the application of membranes to drive bone healing and to exclude non-osteogenic tissues from interfering with bone regeneration. However, the membranes may be exposed to bacterial attack, with the risk of failure of the GBR. Recently, an antibacterial photodynamic protocol (ALAD-PDT) based on a gel with 5% 5-aminolevulinic acid incubated for 45 min and irradiated for 7 min by a LED light at 630 nm, also showed a pro-proliferative effect on human fibroblasts and osteoblasts. The present study hypothesized that the functionalization of a porcine cortical membrane (soft-curved lamina, OsteoBiol) with ALAD-PDT might promote its osteoconductive properties. TEST 1 aimed to verify the response of osteoblasts seeded on lamina with respect to the plate surface (CTRL). TEST 2 aimed to investigate the effects of ALAD-PDT on the osteoblasts cultured on the lamina. SEM analyses were performed to study the topographical characteristics of the membrane surface, the adhesion, and the morphology of cells at 3 days. The viability was assessed at 3 days, the ALP activity at 7 days, and calcium deposition at 14 days. Results showed the porous surface of the lamina and the increase in cell attachment of osteoblasts with respect to controls. The proliferation, the ALP, and bone mineralization activity of osteoblasts seeded on lamina resulted in being significantly higher (p < 0.0001) than controls. Results also showed an additional significative enhancement (p < 0.0001) in the proliferative rate in ALP and calcium deposition after applying ALAD-PDT. In conclusion, the functionalization of the cortical membranes cultured with osteoblasts with the ALAD-PDT improved their osteoconductive properties.

Osteoblasts and Fibroblasts Interaction with a Porcine Acellular Dermal Matrix Membrane.

The use of collagen membranes has remained the gold standard in GTR/GBR. In this study, the features and the biological activities of an acellular porcine dermis collagen matrix membrane applicable during dental surgery were investigated, and also by applying hydration with NaCl. Thus, two tested membranes were distinguished, the H-Membrane and Membrane, compared to the control cell culture plastic. The characterization was performed by SEM and histological analyses. In contrast, the biocompatibility was investigated on HGF and HOB cells at 3, 7, and 14 days by MTT for proliferation study; by SEM and histology for cell interaction study; and by RT-PCR for function-related genes study. In HOBs seeded on membranes, mineralization functions by ALP assay and Alizarin Red staining were also investigated. Results indicated that the tested membranes, especially when hydrated, can promote the proliferation and attachment of cells at each time. Furthermore, membranes significantly increased ALP and mineralization activities in HOBs as well as the osteoblastic-related genes ALP and OCN. Similarly, membranes significantly increased ECM-related and MMP8 gene expression in HGFs. In conclusion, the tested acellular porcine dermis collagen matrix membrane, mainly when it is hydrated, behaved as a suitable microenvironment for oral cells.

Vulnerability Predictors of Post-Vaccine SARS-CoV-2 Infection and Disease-Empirical Evidence from a Large Population-Based Italian Platform.

We aimed to identify individual features associated with increased risk of post-vaccine SARS-CoV-2 infection and severe COVID-19 illness. We performed a nested case-control study based on 5,350,295 citizens from Lombardy, Italy, aged ≥ 12 years who received a complete anti-COVID-19 vaccination from 17 January 2021 to 31 July 2021, and followed from 14 days after vaccine completion to 11 November 2021. Overall, 17,996 infections and 3023 severe illness cases occurred. For each case, controls were 1:1 (infection cases) or 1:10 (severe illness cases) matched for municipality of residence and date of vaccination completion. The association between selected predictors (sex, age, previous occurrence of SARS-CoV-2 infection, type of vaccine received, number of previous contacts with the Regional Health Service (RHS), and the presence of 59 diseases) and outcomes was assessed by using multivariable conditional logistic regression models. Sex, age, previous SARS-CoV-2 infection, type of vaccine and number of contacts with the RHS were associated with the risk of infection and severe illness. Moreover, higher odds of infection and severe illness were significantly associated with 14 and 34 diseases, respectively, among those investigated. These results can be helpful to clinicians and policy makers for prioritizing interventions.

Histologic Evaluation of Soft Tissues around Dental Implant Abutments: A Narrative Review.

The basis for dental implant success comes not only with the titanium implant osseointegration but also depends on other factors such as the development of a soft tissue barrier, which protects the peri-implant bone from the oral environment. The characteristics of surfaces in contact with peri-implant soft tissues may affect the capacity of peri-implant mucosal cells to create a tight seal around the implant, thus influencing long-term implant success. Many histological studies on animals have been conducted on different materials to better understand their influence on peri-implant soft tissues, with the limitation that results from animal studies cannot be fully translated in humans. The aim of this review paper was to analyze the literature focusing on histological clinical studies in humans which have examined different materials or different surface treatments and their effects on peri-implant soft tissues. The research was conducted according to the following PICO question: "Do different implant/abutment materials affect peri-implant soft tissues adhesion and health?". Nine articles were analyzed in this review. The results of this review show the influence of different abutment materials on the peri-implant soft tissues, and the need of further research regarding the effect that abutment materials, surface treatments, and surface properties have on soft tissues.

Consensus Report on Preventive Antibiotic Therapy in Dental Implant Procedures: Summary of Recommendations from the Spanish Society of Implants.

Current patterns of preventive antibiotic prescribing are encouraging the spread of antimicrobial resistance. Recently, the Spanish Society of Implants (SEI) developed the first clinical practice guidelines published to date, providing clear guidelines on how to prescribe responsible and informed preventive antibiotic therapy (PAT) based on the available scientific evidence on dental implant treatments (DIs). The present document aims to summarise and disseminate the recommendations established by this expert panel. These were based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Studies were analysed using the Scottish Intercollegiate Guidelines Network (SIGN) checklist templates and ranked according to their level of evidence. They were then assigned a level of recommendation using the Grading of Recommendations, Assessment, Development and Evaluation system (GRADE). Guidelines were established on the type of PAT, antibiotic and dosage of administration in the placement of DIs without anatomical constraints, in bone augmentation with the placement of DIs in one or two stages, placement of immediate DIs, sinus elevations, implant prosthetic phase, as well as recommendations in patients allergic to penicillin. Therefore, the PAT must be adapted to the type of implant procedure to be performed.

Balancing Benefits and Harms of COVID-19 Vaccines: Lessons from the Ongoing Mass Vaccination Campaign in Lombardy, Italy.

Background. Limited evidence exists on the balance between the benefits and harms of the COVID-19 vaccines. The aim of this study is to compare the benefits and safety of mRNA-based (Pfizer-BioNTech and Moderna) and adenovirus-vectored (Oxford-AstraZeneca) vaccines in subpopulations defined by age and sex. Methods. All citizens who are newly vaccinated from 27 December 2020 to 3 May 2021 are matched to unvaccinated controls according to age, sex, and vaccination date. Study outcomes include the events that are expected to be avoided by vaccination (i.e., hospitalization and death from COVID-19) and those that might be increased after vaccine inoculation (i.e., venous thromboembolism). The incidence rate ratios (IRR) of vaccinated and unvaccinated citizens are separately estimated within strata of sex, age category and vaccine type. When suitable, number needed to treat (NNT) and number needed to harm (NNH) are calculated to evaluate the balance between the benefits and harm of vaccines within each sex and age category. Results. In total, 2,351,883 citizens are included because they received at least one dose of vaccine (755,557 Oxford-AstraZeneca and 1,596,326 Pfizer/Moderna). A reduced incidence of COVID-19-related outcomes is observed with a lowered incidence rate ranging from 55% to 89% and NNT values ranging from 296 to 3977. Evidence of an augmented incidence of harm-related outcomes is observed only for women aged <50 years within 28 days after Oxford-AstraZeneca (being the corresponding adjusted IRR of 2.4, 95% CI 1.1−5.6, and NNH value of 23,207, 95% CI 10,274−89,707). Conclusions. A favourable balance between benefits and harms is observed in the current study, even among younger women who received Oxford-AstraZeneca.

Narrow-diameter versus standard-diameter implants placed in horizontally regenerated bone in the rehabilitation of partially and completely edentulous patients: A systematic review.

PURPOSE: The present systematic review and meta-analysis aimed to investigate the available evidence in the literature to answer the following focused question: In partially edentulous arches with reduced bone width, do implants placed after horizontal bone augmentation exhibit differences in survival and success rate compared to narrow-diameter implants placed in native bone? MATERIALS AND METHODS: A population, intervention, comparison and outcome question was defined and an electronic search was conducted using the MEDLINE (via PubMed) and Cochrane Oral Health Group databases to identify all studies analysing the use of standard-diameter implants inserted in regenerated bone or narrow-diameter implants for the rehabilitation of partially or completely edentulous atrophic maxillae and mandibles. Inclusion criteria and quality assessments were established, and studies were selected on this basis. RESULTS: Twenty-four studies met the inclusion criteria and were analysed cumulatively. A comparative meta-analysis was not possible due to the lack of studies directly comparing the two rehabilitation methods in question. A cumulative implant survival rate of 97.80% (1246/1274; pooled proportion 0.984, 95% confidence interval 0.977-0.991) was reported for the narrow implants placed in atrophic ridges, while similar results were obtained for the standard-diameter implants placed in regenerated bone, with a cumulative implant survival rate of 97.94% (1332/1360; pooled proportion 0.983, 95% confidence interval 0.976-0.990). CONCLUSIONS: The present systematic review found high and comparable survival rates between narrow- and standard-diameter implants placed in regenerated bone; however, well-designed randomised controlled trials are required to support the hypothesis that both treatment strategies are successful in comparable circumstances.

Protective action of natural and induced immunization against the occurrence of delta or alpha variants of SARS-CoV-2 infection: a test-negative case-control study.

BACKGROUND: The evolution of SARS-CoV-2 has led to the emergence of several new variants, and few data are available on the impact of vaccination on SARS-CoV-2 variants. We aimed to assess the association between natural (previous infection) and induced (partial or complete vaccination) exposure to SARS-CoV-2 and the onset of new infection supported by the delta variant, and of comparing it with that supported by alpha. METHODS: We performed a test-negative case-control study, by linking population-based registries of confirmed diagnoses of infection with SARS-CoV-2, vaccinations against Covid-19 and healthcare utilization databases of the Italian Lombardy Region. Four hundred ninety-six persons who between 27 December 2020 and 16 July 2021 had an infection by the delta variant were 1:1 matched with citizens affected by alphavariant and 1:10 matched with persons who had a negative molecular test, according to gender, age and date of molecular ascertainment. We used a conditional logistic regression for estimating relative risk reduction of either variants associated with natural and/or induced immunization and corresponding 95% confidence interval (CI). RESULTS: Previous infection was associated with 91% (95% CI 85% to 95%) reduced relative risk of reinfection, without evidence of significant differences between delta and alpha cases (p=0.547). Significant lower vaccinal protection against delta than alpha variant infection was observed with reduced relative risk associated with partial vaccination respectively of 29% (7% to 45%), and 62% (48% to 71%) (p=0.001), and with complete vaccination respectively of 75% (66% to 82%) and 90% (85% to 94%) (p=0.003). CONCLUSIONS: Lower protection towards infections caused by the delta variant with respect to alpha variant was noticed, even after the completion of the vaccination cycle. This finding would support efforts to maximize both vaccine uptake with two doses and fulfilment with individual protection measures, especially as the delta variant is rampant worldwide presently.

Oral Surgery Procedures in a Patient Affected by Hereditary Angioedema Type I.

Hereditary Angioedema (HAE) is a rare disease characterized by a deficiency or a reduced function of the plasma protein C1 esterase inhibitor (C1-INH), which is involved in the downregulation of several inflammatory pathways. Patients affected by HAE suffer from episodic swellings of subcutaneous or submucosal tissues. Swellings can be caused by stress or dental and surgical procedures and can be life-threatening if the airways are involved. We have reported a clinical case of a patient affected by HAE type I who underwent oral surgery procedures under a short-term prophylaxis with C1-INH plasma-derived concentrate. The patient underwent a cyst removal, multiple tooth extractions, and an excisional biopsy with a prophylaxis with C1-INH plasma-derived concentrate and was hospitalized for 36 hours after the surgery to be monitored for possible HAE attacks. During the hospitalization, the patient did not show signs of swelling nor of HAE attacks. At 14 and 28 days after the surgery, the patient presented a good surgical healing. The prophylactic intravenous infusion of C1-INH concentrate was successful in preventing acute HAE attacks after oral surgery procedures.

Persistence of protection against SARS-CoV-2 clinical outcomes up to 9 months since vaccine completion: a retrospective observational analysis in Lombardy, Italy.

BACKGROUND: Scarce information is available on the duration of the protective effect of COVID-19 vaccination against the risk of SARS-CoV-2 infection and its severe clinical consequences. We investigated the effect of time since vaccine completion on the SARS-CoV-2 infection and its severe forms. METHODS: In this retrospective observational analysis using the vaccination campaign integrated platform of the Italian region of Lombardy, 5 351 085 individuals aged 12 years or older who received complete vaccination from Jan 17 to July 31, 2021, were followed up from 14 days after vaccine completion until Oct 20, 2021. Changes over time in outcome rates (ie, SARS-CoV-2 infection and severe illness among vaccinated individuals) were analysed with age-period-cohort models. Trends in vaccine effectiveness (ie, outcomes comparison in vaccinated and unvaccinated individuals) were also measured. FINDINGS: Overall, 14 140 infections and 2450 severe illnesses were documented, corresponding to incidence rates of 6·7 (95% CI 6·6-6·8) and 1·2 (1·1-1·2) cases per 10 000 person-months, respectively. From the first to the ninth month since vaccine completion, rates increased from 4·6 to 10·2 infections, and from 1·0 to 1·7 severe illnesses every 10 000 person-months. These figures correspond to relative reduction of vaccine effectiveness of 54·9% (95% CI 48·3-60·6) for infection and of 40·0% (16·2-57·0) for severe illness. The increasing infection rate was greater for individuals aged 60 years or older who received adenovirus-vectored vaccines (from 4·0 to 23·5 cases every 10 000 person-months). The increasing severe illness rates were similar for individuals receiving mRNA-based vaccines (from 1·1 to 1·5 every 10 000 person-months) and adenovirus-vectored vaccines (from 0·5 to 0·9 every 10 000 person-months). INTERPRETATION: Although the risk of infection after vaccination, and even more of severe illness, remains low, the gradual increase in clinical outcomes related to SARS-CoV-2 infection suggests that the booster campaign should be accelerated and that social and individual protection measures against COVID-19 spread should not be abandoned. FUNDING: None.