Safety And Seroconversion Of Immunotherapies Against SARS-CoV-2 Infection: A Systematic Review And Meta-Analysis Of Clinical Trials Part 2

2.1.2. Inactivated and Subunit Vaccines Allowing for Active Immunity

Vaccination, as a process, could also induce active immunity or immunological memory, followed by a prophylactic effect on specific pathogens. Those defending the infected individuals through such a mechanism include killed or inactivated, toxoid, subunit, and live-attenuated vaccines. 

Vaccination is currently one of the most effective methods of preventing infectious diseases. By injecting vaccines, the body generates an immune response against the pathogen, thereby enhancing the body's ability to resist disease.

Vaccination not only protects the health of individuals but also the health of entire communities. When enough people are vaccinated, herd immunity develops, stopping the disease from spreading in the community and thus protecting those who cannot be vaccinated.

The Drug Administration ensures the safety and effectiveness of vaccines by conducting comprehensive and strict reviews and supervision of vaccines. Multiple clinical trials and large-scale vaccination practices have proven that vaccination is a safe and reliable method to prevent diseases.

Although vaccination can strengthen the body's immunity, it does not guarantee complete immunity. Because disease pathogens mutate from time to time, there are no vaccines to prevent some diseases. Therefore, we need to maintain good hygiene habits at all times, stay healthy, and prevent diseases through vaccination.

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Among them, trials of killed or inactivated, and subunit vaccines against COVID-19 are still in early phases due to safety concerns. 

Trials aiming at inducing active immunity in healthy individuals include inactivated virus vaccines including inactivated virus (n = 42, total participants = 232,899) and S protein-derived subunit vaccines such as recombinant S protein vaccines (n = 49, participants = 172,232), mRNA vaccines (n = 68, total participants = 162,052), DNA vaccines (n = 13, participants = 8481), viral vector-based vaccines (n = 70, participants = 271,524), virus-like particles (n = 5, participants = 31,050), and live recombinant bacterial vectors (n = 1, participants = 84). Moreover, one of these trials evaluated the safety and antibody response of live-attenuated SARS-CoV-2 vaccines (participants = 48).

2.1.3. Convalescent Plasma or Immunoglobulin Transfer Providing Passive Immunity

Among these trials aiming at transferring passive immunity, 18 trials administered intravenous immunoglobulin (participants = 2756), and 41 trials implemented convalescent plasma (participants = 13,864). 

In particular, 11 trials were in phase 3, and 1 trial was in phase 4, all of which revealed the therapeutic potential of immediate transfer of humoral immunity in COVID-19 patients.

2.1.4. Immunotherapy

Immune checkpoint inhibitors such as PD-1 inhibitors and neutralizing antibodies have been widely used as immunotherapy agents [11]. Overreaction of the immune system has been reported to drive severe COVID-19 disease progression [12]. 

There were 29 trials (total participants = 3547) that evaluated immune checkpoint inhibitors including anti-PD-1 inhibitors such as nivolumab, anti-component 5a receptor (C5aR) monoclonal antibodies such as avdoralimab, and anti-IL6R neutralizing antibodies such as tocilizumab. 

Specifically, nivolumab was used to alleviate (cytotoxic T) T cell exhaustion that arose during SARS-CoV-2 infections [13], whereas avdoralimab and tocilizumab were expected to blockC5a/C5aR and IL6-IL6R pathways, which could bring about protective adaptive immunity [14] and block exuberant inflammation in COVID-19 pathogenesis [15]. 

On the other hand, immunotherapies aimed at increasing virus-eliminating immune pathways via the transfer of protective cytokines have been proposed. There were 14 trials (participants = 2329) that used cytokines such as IL-2 and IL-7 for lymphocyte activation [16] or type I IFNs to induce innate immunity against virus infections [17]. Ongoing trials on immune cell transfer (n = 16, participants = 1112) include the transplantation of lentivirus-modified DCs, antigen-loaded DCs, allogeneic natural killer (NK) cells, NK cells modified by CAR (NKG2D-ACE2 CAR-NK Cells), all of which were of phase 1 or 1&2, aiming at evaluating safety performance.

2.2. Meta-Analysis of Trial Reports

There were 9072 participants among the 27 studies included in the meta-analysis (Table 3). AEs in all studies were evaluated. The time from designated intervention to venipuncture for seroconversion was restricted to 28 days post-vaccination to verify that the immune response was rapid and specifically against the SARS-CoV-2 virus. The key characteristics and details of all included studies were described in Supplementary Table S2.

Overall safety of the subunit vaccines, defined as the inverse ORs of solicited systemic reactions, was derived for solicited systemic reactions of protein-based (Figure 2A, pooled inverse OR 0.53, 95% CI 0.27 to 1.05; p = 0.07), RNA-based (Figure 2B, pooled inverse OR 0.35, 95% CI 0.16 to 0.75; p = 0.007), and viral vector-based (Figure 2C, pooled inverse OR 0.32, 95% CI 0.19 to 0.55; p < 0.0001) vaccines, and overall safety of inactivated vaccines were derived for inactivated virus-based vaccines (Figure 2D, pooled inverse OR 1.00, 95% CI 0.73 to 1.36; p = 0.98). 

Risks of solicited local reactions were derived for protein vaccines (Figure S2A, pooled inverse OR 0.12, 95% CI 0.06 to 0.24; p < 0.00001), RNA vaccines (Figure S2B, pooled inverse OR 0.04, 95% CI 0.02 to 0.07; p < 0.00001), viral vector vaccines (Figure S2C, pooled inverse OR 0.24, 95% CI 0.09 to 0.64; p = 0.04), and inactivated virus vaccines (Figure S2D, pooled inverse OR 0.46, 95% CI 0.29 to 0.72; p = 0.04) in which all four types of vaccine products can induce significant local AEs, compared with placebo/control. 

Risks of unsolicited AEs were derived for protein vaccines (Figure S3A, pooled inverse OR 0.90, 95% CI 0.60 to 1.34; p = 0.6), viral vector vaccines (Figure S3B, pooled inverse OR 0.48, 95% CI 0.30 to 0.77; p = 0.003), and inactivated virus (Figure S3C, pooled inverse OR 0.73, 95% CI 0.32 to 1.66; p = 0.46), while there was only one study addressing all unsolicited AEs for RNA vaccines [25].

Vaccination-mediated immune responses against SARS-CoV-2 were defined as seroconversion of at least a fourfold increase in the titers of neutralized antibodies against viral infection [45]. All vaccines can promptly induce seroconversion to block SARS-CoV-2 infection within 28 days post-vaccination. 

The seroconversion was derived for protein vaccines (Figure 3A, pooled OR 13.94, 95% CI 1.87 to 103.65; p = 0.01), RNA vaccines (Figure 3B, pooled OR 84.86, 95% CI 13.63 to 528.21; p < 0.00001), viral vector vaccines (Figure 3C, pooled OR 106.03, 95% CI 40.73 to 276.03; p < 0.00001), and inactivated virus vaccines (Figure 3D, pooled OR 451.04, 95% CI 108.53 to 1874.5; p < 0.00001). 

These findings suggest that both protein vaccines and inactivated virus vaccines are more tolerable and safer than RNA vaccines, followed by viral vector vaccines and that inactivated vaccines have the highest efficacy to rapidly elicit serological responses, followed by viral vector vaccines, than RNA vaccines, and finally, protein vaccines based on their pooled ORs.

3. Discussion

In this systematic review of 389 clinical trials from the NIH Clinical Trial Database and meta-analysis of 27 published reports of the abovementioned trials, as well as one report for trials from the Chinese Clinical Trial Registry, an increasing number of immune-augmentative therapies for COVID-19 was observed. 

Moreover, the paradigm in this field has been gradually shifting from off-label use of irrelevant vaccines to active immunity induction against SARS-CoV-2, due mainly to their capabilities of providing specific protective immunity against SARS-CoV-2. 

In our systematic review, immuno-augmentative therapies presented promising immunogenicity and capabilities of reinforcing neutralized antibodies, which realized protective immunity against SARS-CoV-2 but at the same time addressed solicited systemic adverse reactions, solicited local adverse reactions, and unsolicited multiple organ adverse reactions.

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