Results from two early-phase Russian non-randomised vaccine trials (Sputnik V) in a total of 76 people are published today in The Lancet, finding that two formulations of a two-part vaccine have a good safety profile with no serious adverse events detected over 42 days, and induce antibody responses in all participants within 21 days.
Secondary outcomes (planned outcome measures that are not as important as the primary outcome measure, but are still of interest in evaluating the effect of an intervention from the trial also suggest the vaccines also produce a T-cell response within 28 days.
The new paper reports the findings from two small phase 1/2 trials lasting 42 days -- one studying a frozen formulation of the vaccine, and another involving a lyophilised (freeze-dried) formulation of the vaccine. The frozen formulation is envisaged for large-scale use using existing global supply chains for vaccines, while the freeze-dried formulation was developed for hard-to-reach regions as it is more stable and can be stored at 2-8 degrees centigrade.
The two-part vaccine includes two adenovirus vectors - recombinant human adenovirus type 26 (rAd26-S) and recombinant human adenovirus type 5 (rAd5-S) -- which have been modified to express the SARS-CoV-2 spike protein. The adenoviruses are also weakened so that they cannot replicate in human cells and cannot cause disease (adenovirus usually causes the common cold).
These types of recombinant adenovirus vectors have been used for a long time, with safety confirmed in many clinical studies. Currently, several candidate COVID-19 vaccines using these vectors and targeting the SARS-CoV-2 spike protein have been tested in clinical trials. These vaccines aim to stimulate both arms of the immune system - antibody and T cell responses - so they attack the virus when it is circulating in the body, and attack cells infected by SARS-CoV-2 .
Explaining why they are using two different adenovirus vectors, lead author Dr. Denis Logunov, N F Gamaleya National Research Centre for Epidemiology and Microbiology, Russia, says, "When adenovirus vaccines enter people's cells, they deliver the SARS-CoV-2 spike protein genetic code, which causes cells to produce the spike protein. This helps teach the immune system to recognise and attack the SARS-CoV-2 virus. To form a powerful immune response against SARS-CoV-2, it is important that a booster vaccination is provided. However, booster vaccinations that use the same adenovirus vector might not produce an effective response, because the immune system may recognise and attack the vector. This would block the vaccine from entering people's cells and teaching the body to recognise and attack SARS-CoV-2. For our vaccine, we use two different adenovirus vectors in a bid to avoid the immune system becoming immune to the vector."
The trials took place in two hospitals in Russia. The trials were open-label and non-randomised, meaning that participants knew that they were receiving the vaccine and were not assigned by chance to different treatment groups.
The trials involved healthy adults aged 18-60 years, who self-isolated as soon as they were registered for the trial and remained in hospital for the first 28 days of the trial (from when they were first vaccinated).
The frozen vaccine (Gam-COVID-Vac) was trialled in a branch of Burdenko Hospital, an agency of the Ministry of Defence, and involved both civilian and military volunteers. The freeze-dried vaccine (Gam-COVID-Vac-Lyo) took place at Sechenov University and all volunteers were civilians. All participants provided written informed consent.
In the phase 1 of each trial, participants received one component of the two-part vaccine on day 0 (four groups of nine participants were given the frozen or freeze-dried rAd26-S or rAd5-S component - see Figure 1). In the phase 2, which began no earlier than five days after the phase 1 trial began, participants received the full two-part vaccine (they received a prime vaccination with the rAd26-S component on day 0, followed by a booster vaccination with rAd5-S component on day 21. There were 20 participants each in the frozen and freeze-dried vaccine groups).
The trial was designed to study the number of adverse events of the vaccines (safety), and the antibody response elicited by the vaccines (immunogenicity). Secondary outcome measures of the trials  included the neutralising antibody response and the T cell response elicited. To compare post-vaccination immunity with natural immunity formed by infection with SARS-CoV-2, the authors obtained convalescent plasma from 4,817 people who had recovered from mild or moderate COVID-19.
Both vaccine formulations were safe over the 42-day study period and well tolerated. The most common adverse events were pain at injection site (44/76 participants - 58%), hyperthermia (high temperature - 38/76 - 50%), headache (32/76 - 42%), asthenia (weakness or lack of energy - 21/76 - 28%), and muscle and joint pain (18/76 - 24%). Most adverse events were mild, and no serious adverse events were detected within 42 days of vaccination. The authors note that these adverse effects are characteristic of those seen with other vaccines, particularly those based on recombinant viral vectors.
All participants in the phase 2 trials (40 participants) produced antibodies against the SARS-CoV-2 spike protein - with levels of antibody against the SARS-CoV-2 spike protein (geometric mean titres of SARS-CoV-2 receptor binding domain-specific IgG) at 14,703 for the frozen formulation, and at 11,143 for the freeze-dried formulation on day 42 of the trial.
In addition, neutralising antibody responses occurred in all 40 participants in the phase 2 trials by day 42 (geometric mean titre levels of 49.25 with the frozen formulation and 45.95 with the freeze-dried formulation at day 42), whereas neutralising antibody responses were only found in 61% of participants in the phase 1 study who only received rAd26-S (combined data for both the lyophilised and frozen vaccine formulations).
Comparing the antibody responses from the vaccination and from infection (using the convalescent plasma samples), the authors say that the antibody responses from vaccination appear to be higher in people vaccinated. Vaccination also elicited the same level of SARS-CoV-2 neutralising antibodies as in people who had recovered from COVID-19.
T cell responses occurred in all participants in the phase 2 trials within 28 days of vaccination - including formation of T-helper (CD4) cells and T-killer (CD8) cells. The number of T-helper cells increased by 2.5% and the number of T-killer cells increased by 1.3% after vaccination with the frozen formulation, and by 1.3% and 1.1%, respectively, after vaccination with the freeze-dried formulation.
The authors say that despite there being neutralising antibody responses against the adenovirus vectors, the antibody response to the SARS-CoV-2 spike protein was not affected. In addition, the neutralising antibodies against rAd26 did not interfere with rAd5, or vice versa. They say that this suggests that using different adenovirus vectors is an effective approach to elicit a robust immune response and to overcome the immune reaction to the first viral vector, but note that more research will be needed to confirm this.
The authors note some limitations to their study, including that it had a short follow-up (42 days), it was a small study, some parts of the phase 1 trials included only male volunteers, and there was no placebo or control vaccine. In addition, they note that despite planning to recruit healthy volunteers aged 18-60 years, in general, their study included fairly young volunteers (in their 20s and 30s, on average).
They say that more research is needed to evaluate the vaccine in different populations, including older age groups, individuals with underlying medical conditions, and people in at-risk groups.
Explaining the next steps of their research, Professor Alexander Gintsburg, N F Gamaleya National Research Centre for Epidemiology and Microbiology, Russia, says: "Unprecedented measures have been taken to develop a COVID-19 vaccine in Russia. Preclinical and clinical studies have been done, which has made it possible to provisionally approve the vaccine under the current Decree of the Government of the Russian Federation of April 3, 2020 no 441. This provisional licensure requires a large-scale study, allows vaccination in a consented general population in the context of a phase 3 trial, allows the vaccine to be brought into use in a population under strict pharmacovigilance, and to provide vaccination of risk groups." 
"The phase 3 clinical trial of our vaccine was approved on 26 August 2020. It is planned to include 40,000 volunteers from different age and risk groups, and will be undertaken with constant monitoring of volunteers through an online application." 
Writing in a linked Comment, lead author Dr Naor Bar-Zeev, International Vaccine Access Center, Johns Hopkins Bloomberg School of Public Health, (who was not involved in the study), says: "Similar to these studies before it, Logunov and colleagues' studies are encouraging but small. The immunogenicity bodes well, although nothing can be inferred on immunogenicity in older age groups, and clinical efficacy for any COVID-19 vaccine has not yet been shown... Showing safety will be crucial with COVID-19 vaccines, not only for vaccine acceptance but also for trust in vaccination broadly. Safety outcomes up to now are reassuring, but studies to date are too small to address less common or rare serious adverse events. Unlike clinical trials of therapeutics, in which safety is balanced against benefit in patients, vaccine trials have to balance safety against infection risk, not against disease outcome. Since vaccines are given to healthy people and, during the COVID-19 pandemic, potentially to everyone after approval following phase 3 trials, safety is paramount..."
"Licensure in most settings should depend on proven short-term and long-term efficacy against disease (not just immunogenicity) and more complete safety data... Safety assurance will then require further large-scale surveillance after licensure. Such surveillance is not well established in many settings, and rapid efforts need to be made by governments, regulators, and global research funders to get those systems in place. Surveillance will also be vital for showing transmission reduction, which is to come from phase 3 trials since these are powered to detect COVID-19 disease outcomes and not asymptomatic SARS-CoV-2 infection. To be sure, most past vaccines were designed to target disease and not infection as such, but with COVID-19, the general public could be expecting striking reductions in disease transmission after widespread vaccine introduction. Such effects would be very welcome if they occur, but they are far from certain. A vaccine that reduces disease but does not prevent infection might paradoxically make things worse. It could falsely reassure recipients of personal invulnerability, thus reducing transmission mitigating behaviors. In turn, this could lead to increased exposure among older adults in whom efficacy is likely to be lower, or among other higher-risk groups who might have lower vaccine acceptance and uptake."
"In view of the ongoing painful toll of the COVID-19 pandemic and its magnitude, the more vaccine candidates that have successful early results the better. Ultimately, all vaccine candidates will need to show safety and prove durable clinical efficacy (including in groups at greater risk) in large randomized trials before they can be put into widespread use. Equitable access will require multiple vaccine producers and providers in a range of settings. Each of their successes will together lead us towards our collective, longed for, new day."
This study was funded by the Ministry of Health of the Russian Federation. It was conducted by researchers from the Ministry of Health of the Russian Federation and the Ministry of Defense of the Russian Federation.
Source: The Lancet