A vaccine against COVID-19: steps and results from clinical trial phase 1
Since the end of 2019, cascades of news about SARS-CoV-2 infection have spread one after the other, thick and fast. However, one of the most awaited will be the eventual news of a vaccine, proven to be safe and effective, that will allow us to protect ourselves from the virus. Recognizing that the path until then will certainly be long, time-consuming and demanding, scientists from around the world have been joining efforts to increase the knowledge about this virus and also concerning how the immune system establishes its responses to this challenging infection.
The authors of the article recently published in The Lancet present important data for the continuity of this demand, with results from the first human trial of a recombinant vaccine for COVID-19. This vaccine, one of more than 100 candidates currently under development, is a modified adenovirus, with no replication capacity, but which allows the expression of the “famous” glycoprotein S (spike) from SARS-CoV-2. In order to be approved, the vaccine will have to pass strict safety criteria and prove to be capable of inducing the desired protective immunity. The work presented at The Lancet exposes one of the stages of this process, a phase 1 clinical trial.
For this purpose, researchers recruited participants without previous contact with SARS-CoV-2, evidenced by the absence of serum IgG and IgM antibodies to the virus (serological tests), absence of viral nucleic acids in respiratory and nasal samples (PCR test), and absence of lung lesions assessed by X-ray examination. Sequentially, three groups of participants were established, to whom the vaccine was administered, by intramuscular injection, in low, medium or high dose. In order to allow the early recognition of potential adverse effects, which would limit the continuity of the study, the first group of participants (low dose of the vaccine) was followed for three days, and only then began the recruitment of the second group, which would receive the intermediate dose. The second group was also followed up for three days post-vaccine, before the third group was recruited, the one that would receive the high dose. All participants were monitored for 28 days.
In this phase 1 trial, the goal was to assess the tolerability of individuals to the vaccine, as well as to evaluate their ability to induce humoral immunity (by the presence of antibodies) and to stimulate cellular immune responses, assumed by specialized populations of lymphocytes, T cells .
As for tolerability, local and systemic effects were assessed. About half of the patients in each group reported pain in the injection area (54%). At the systemic level, the most frequent complaints were fever (46%), fatigue (44%), headache (39%) and muscle pain (17%). Overall, there were no significant differences in adverse reactions between groups, although the high dose of the vaccine has led some patients to present more severe side effects. In general, the manifestations were mild to moderate, transient and self-limited, very similar to those observed in other vaccines with the same vector (common tool used in molecular biology to deliver material, such as DNA or genes, into cells). Some biomarkers, such as liver enzymes, were monitored throughout the study, with no clinically significant changes in the three groups. Nonetheless, these apparent good indicators, from the point of view of tolerability, still require more extended studies to allow for definitive and consistent decisions to be made about the safety of the vaccine.
Regarding the immune approach, antibody titers against the virus were evaluated, as well as its neutralizing action, which attests to its potential effectiveness. After administration of the vaccine, anti-SARS-CoV2 antibodies were identified in the serum on the 14th day, reaching its peak on the 28th day, regardless of the dose of vaccine administered. Nevertheless, the highest antibody titers for different components of the virus were identified in the group that received the highest dose of the vaccine.
The cellular response is vital for the immune response and is therefore an element that cannot be overlooked in the (clinical) evaluation of vaccines. Especially when long-term immunity is sought, which is substantially ensured by a network of memory cells, in constant communication and surveillance. Thus, the results observed in this study for cellular response are also important.
Upon stimulation, circulating T cells produce cytokines, which are small mediators crucial for the orchestration of immune responses. At the time of vaccine administration, T cells from the study participants were isolated and exposed in vitro to viral proteins and showed no response. However, on days 14 and 28 post-vaccination, the procedure was repeated, and a T cell response with cytokine production was clearly identified after cell incubation with the viral proteins. Here, the peak of response was achieved earlier, somehow preceding the humoral response, which is in fact oriented by the T-cell profile. The boom of the cellular response (revealed by the increased production of Interferon-gamma, TNF-alpha or Interleukin-2) was established on the 14th day post-vaccination, in all groups. However, responses were somehow limited in the group administered with the low dose of the vaccine, as shown by the ELISpot assays and the evaluation by Flow Cytometry.
Despite the promising elements considering both the potential application and the type of response generated, there are still some challenges to surpass when exploring the results of the study. The scarce number of participants (only 36 per group, without a control group) and monitoring time (only 28 days post vaccine), are limitations that phase 2 trials will complement, for both vaccine safety issues and the continuity of responses beyond this period. On the other hand, although the vector used (Ad5) is already well-established in immunization protocols, it seems important to clarify the observations of this study suggesting the presence of previous immunity against the vector itself interferes with the level of anti-SARS-CoV-2 specific response generated (humoral and cellular), though not totally preventing it.
In conclusion, the vaccine studied by the authors proved to be well tolerated and immunogenic, that is, capable of inducing an immune response, humoral and cellular, without generating significant adverse effects. The study shows that T cells respond 14 days after the vaccine is administered, and about one month after the vaccine antibodies with potential for viral neutralization can also be found. These promising results sustain the necessity to continue the study, which is already underway, by monitorization of the groups up to six months post vaccine, but also taking the next step, with a phase 2 trial, to which low and intermediate doses of the vaccine have been selected (effective and less reactogenic than the high dose).
Contributing scientist: Catarina Martins
Translation: Catarina Martins e Maria Serrano
Scientific paper: Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial