ABSTRACT
In the early seventeenth century, smallpox was one of the most fearsome communicable diseases in the world. Lady Mary Montagu noted that the disease could be prevented by introducing liquid extracted from smallpox scabs from an infected patient into the skin of healthy individuals. This process, known as “variolation” was used in England and in USA until the first investigations by the English physician Edward Jenner appeared. Jenner created the vaccine for an animal poxvirus from the pustule formed by the vaccinia virus in the teats of cows, where the technique was essentially based on the idea that a virulent agent for animals could be attenuated in humans. In 1885, Louis Pasteur, through a fixed virus which was obtained by successive passages in the nervous tissue of rabbits with the dissecting action of potassium hydroxide, developed the vaccine against rabies, in which similar procedures were adopted in the development of several vaccines of live attenuated viruses. Already in the 1940s, a revolution occurred with the discovery that cells could be cultured in vitro and used as substrates for viral growth. Oral polio vaccine and vaccines against measles, rubella, mumps and chickenpox were made possible by selecting clones by passage in in vitro cell culture. Some RNA virus have segmented genomes that can be manipulated. Co-cultivation of two virus in cell culture with clone selection by plaque formation allows the isolation of virus with segments from both. This regrouping planned to create three main vaccines: live and inactivated influenza as well as one of two rotavirus vaccines. Another discovery in the late nineteenth century was that immunogenicity could be maintained as the substance contained in those killed by heat or chemical treatment. This type of inactivation was first applied to pathogens of typhoid fever, plague and cholera bacilli. In the twentieth century, chemical inactivation was also applied to a virus. The influenza vaccine was the first successful inactivated virus vaccine, developed against Polio and Hepatitis A. Besides, several vaccines consist of partially or fully purified proteins. Most of the inactivated flu vaccines used are created by growing the virus in embryonated eggs and then breaking down the entire virus with detergents. The viral hemagglutinin protein is purified to serve as the vaccine antigen, although other influenza virus components may be part of the final product. Early in the history of bacteriology, morphological studies and chemical analyzes showed that many pathogens were surrounded by a polysaccharide capsule and that antibodies against the capsule could promote phagocytosis. The first use of this information to create a vaccine was the development of the meningococcal polysaccharide vaccine. After years of study and development in bacterology, the scientific community faced the Covid-19 pandemic in 2020, marked by the race against time in the invention of effective vaccines against the SARS-CoV-2 virus. After all, most of vaccines take more than a decade to be formulated and, in the case of the vaccine against the new coronavirus, in less than a year, at least 34 candidate vaccines appeared in clinical analysis. New vaccine production techniques using DNA and RNA recombination techniques are being implemented in this race. In Brazil, the most widely distributed vaccines approved by Anvisa are AstraZeneca, CoronaVac and Pfizer-BioNTech. The AstraZeneca/Oxford vaccine is composed of a non-replicating viral vector, which consists of a defective chipamzee virus (adenovirus), with a segment of the SARS-CoV-2 genome, responsible for producing the structure present on the viral surface (protein S), being recognized by human cells, triggering an immune response against Coronavirus. The CoronaVac vaccine is composed by the inactivated SARS-CoV-2 virus, along with its complete structure. It is unable to multiply, although it can stimulate the response to produce antibodies. The Pfizer-BioNTech vaccine, on the other hand, consists of a formulated lipid nanoparticle of nucleoside-modified mRNA that encodes the pre-fusion peak glycoprotein of SARS-CoV-2. Despite the small amount of dose applications in Brazil, the Janssen vaccine has recently started its distribution in the country. This is the only vaccine, so far, with a single dose application. It is an adenovirus 26 (Ad26) vector vaccine that contains in its interior genetic material of the S protein contained in the surface spikes of SARS-CoV-2, and that stimulates, after application, the cellular responses of T CD4 + and T CD8 + antibodies. Here, we propose a detailed review of the entire history of vaccination, from Smallpox to Covid-19. © 2022, The Author(s), under exclusive license to Springer Nature Switzerland AG.
ABSTRACT
Background: The Phase III PROpel (NCT03732820) trial demonstrated at interim analysis a statistically significant clinical benefit from combining ola + abi in the first-line (1L) mCRPC setting vs placebo (pbo) + abi. Benefit was seen irrespective of a pt's homologous recombination repair mutation (HRRm) status;median radiographic progression-free survival (rPFS) 24.8 for ola + abi vs 16.6 months for pbo + abi (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.54-0.81;P<0.0001). The safety profile of ola + abi was shown to be consistent with that for the individual drugs. We report additional interim safety analysis from PROpel. Methods: Eligible pts were ≥18 years with mCRPC, had received no prior chemotherapy or next-generation hormonal agent treatment at mCRPC stage, and were unselected by HRRm status. Pts were randomized 1:1 to abi (1000 mg qd) plus prednisone/prednisolone with either ola (300 mg bid) or pbo. Primary endpoint was investigator-assessed rPFS. Safety was assessed in all pts receiving ≥1 dose of study treatment by adverse event (AE) reporting (CTCAE v4.03). Results: 398 pts received ola + abi and 396 pbo + abi (safety analysis set). At data cut-off (July 30, 2021), median total duration of exposure for ola was 17.5 vs 15.7 months for pbo, and for abi 18.2 months in the ola + abi arm and 15.7 in the pbo + abi arm. Anemia (n=183) was the most common AE in the ola + abi arm, and 34% of these 183 events were managed by dose interruption, 23% by dose reduction, and 8% resulted in treatment discontinuation. Anemia and pulmonary embolism (PE) were the only Grade ≥3 AEs in ≥5% of pts (anemia: ola + abi, 15.1% vs pbo + abi, 3.3%;PE: 6.5% vs 1.8%, respectively). Most PEs were detected incidentally on radiographic imaging (69.2% and 71.4% in the ola + abi and pbo + abi arms, respectively) and no pts discontinued. More pts in the ola + abi arm experienced venous thromboembolism (Table). Arterial thromboembolism and cardiac failure AEs were balanced between the treatment arms. No AE of myelodysplastic syndrome/acute myeloid leukemia was reported in either treatment arm. COVID-19 was reported more frequently with ola + abi (8.3% vs 4.5%). Conclusions: PROpel demonstrated a predictable safety profile for ola + abi given in combination to pts with 1L mCRPC unselected by HRRm status. AEs of cardiac failure and arterial thromboembolism were reported at similar frequency in both treatment arms. The majority of PEs were asymptomatic. The safety profile of abiraterone was not adversely impacted by its combination with olaparib.
ABSTRACT
Background: PSMA is a transmembrane glycoprotein overexpressed in prostate cancer (PC) and further upregulated in castrate resistant disease. 1095 is a novel PSMA-targeted small molecule radioligand therapeutic that binds to the extracellular domain of PSMA selectively with high affinity, internalized, and delivers a targeted lethal radiation dose to PC cells. F-DCFPyL is a novel PSMA-targeted PET imaging agent that has shown robust diagnostic performance for detecting recurrent and metastatic PC. In the ARROW study, pts must demonstrate F-DCFPyL avidity prior to 1095 treatment. Methods: ARROW is an openlabel, randomized (2:1) trial of enza plus 1095 or enza alone in pts with progressive mCRPC who previously received abi. ∼120 pts (80: 1095 + enza;40: enza alone) will be treated at multiple sites in the US and Canada. Eligible male pts must have metastatic disease documented by bone scan or soft tissue lesions measurable per RECIST 1.1 on CT/MRI, be PSMA-avid as determined by FDCFPyL PET/CT, have evidence of biochemical or radiographic progression on abi, and be ineligible for or refuse to receive chemotherapy. Pts will receive enza (prescribed per approved labeling) with or without 1095 (100 mCi dose, followed by up to 3 additional doses administered at least 8 weeks apart, as determined by dosimetry evaluation and occurrence of dose-limiting events). The primary objective is to determine the efficacy of 1095 plus enza compared to enza alone, based on PSA response (confirmed PSA decline ≥50%) rate according to Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria. Additional objectives include objective response rate based on PCWG3-modified RECIST 1.1, progression-free survival (PFS) defined as the first occurrence of radiographic progression (PCWG3-modified RECIST 1.1), unequivocal clinical progression, or death from any cause, duration of response, overall survival, and the safety and tolerability of 1095 radioligand therapy. Due to the COVID-19 pandemic, enrollment was halted in April 2020 but is reopening in October 2020. Clinical trial information: NCT03939689.