key: cord-0927058-1h8c4yq9
authors: LOCHT, Camille
title: Vaccines against COVID-19
date: 2020-10-20
journal: Anaesth Crit Care Pain Med
DOI: 10.1016/j.accpm.2020.10.006
sha: 67b314fe142778f3be3adca98489d573e9454df5
doc_id: 927058
cord_uid: 1h8c4yq9

nan

for SARS-CoV-2 5 , it has been demonstrated for dengue 3 . One way to overcome this potential risk is to include antigens/epitopes that generate cell-mediated immunity, particularly via CD8 + T cells. This has been shown protective against dengue, even in the presence of diseaseenhancing antibodies 6 . Especially tissue-resident memory CD8 + T cells generated in the upper airways may be important for long-lasting protection, as has been shown for influenza 7 .

Several hundred COVID-19-specific vaccines are at various stages of development in academia and industry and make use of a variety of different generic platforms, such as inactivated virus, purified recombinant viral proteins with or without adjuvant, replicating and non-replicating viral vectored antigens, antigen-encoding DNA or mRNA. Some of them build on technologies approved for other vaccines, others are novel and have not yet been used for large-scale vaccination. This editorial will focus on vaccines in clinical development with data published in peer-reviewed articles.

The first clinical trial data were published in June 2020 8 . The trial was a dose-escalation study of recombinant adenovirus type-5 vectored S. The vaccine was shown tolerable, although 75-83% of participants reported adverse events, mostly mild or moderate. It induced neutralising antibody and T cell responses with seroconversion in 50-75% of the vaccine recipients. However, pre-existing vector-neutralising antibodies diminished the immune responses. Furthermore, immunogenicity was sub-optimal in older participants. This study was followed by a phase 2, randomised, double-blind trial 9 , including 508 participants. Sero-conversion was seen in more than 95% and neutralising antibodies were generated in 85% of vaccine recipients. IFN- responses were also seen in roughly 90% of the vaccinees. Again, the vaccine induced lower antibody responses in older participants and subjects with pre-existing antivector immunity. The vaccine at a 5x10 10 viral particles/ml dose is now in a phase 3 trial in Brazil.

To overcome the immune-interference by pre-existing immunity to the vector, a replicationdeficient simian adenovirus-vectored vaccine was engineered to encode S. A phase 1/2, singleblind, randomised controlled study with this vaccine at 5x10 10 viral particles/ml in 1077 healthy adults showed acceptable safety 10 . Local and systemic reactions were frequent but could be reduced by paracetamol. The vaccine also induced T cell and antibody responses, including virus-neutralising antibodies. After a booster given to some participants, antibody responses increased neutralising antibodies were generated in all participants. This vaccine is currently in phase 3 in several countries. A combination of two adenovirus-vectored vaccines (types 26 and 5), both carrying S, was tested in a non-randomised, non-placebo-controlled phase 1/2 trial in a total of 38 volunteers in Russia 11 . In phase 1, each vaccine was tested individually, followed by phase 2, in which the participants were primed with rAd26 and boosted with rAd5. The two studies combined included 38 volunteers. Adverse events included injection-site pain in 58% of the participants, as well as hyperthermia, headache, asthenia, and muscle and joint pain. All participants generated high titres of IgG recognising the receptor-binding domain of S. Neutralising titres were also induced, as well as CD4 + and CD8 + T cell responses. Although safety and immunogenicity reported in this study were in line with the previous studies on adenovirusvectored vaccines, this study has raised concerns about the validity of the reported results, especially in the context of potential accelerated distribution of the vaccine in the population in Russia 12 .

An inactivated, alum-adjuvanted whole-virus vaccine has also undergone a phase 1/2 trial 13 . In phase 1 with 96 participants, three intramuscular injections of 2.5, 5 and 10 µg/dose were compared to alum, followed by phase 2 with 224 participants comparing two injections of 5 µg/dose with alum. Adverse reactions, mild and self-limiting injection site pain and fever occurred in 9 to 20.8% of vaccine recipients and were not more frequent than in the alum control group. The geometric mean titres of neutralising antibodies ranged from 121 to 316.

Two RNA-based vaccines are currently in phase 3, mRNA-1273 and BNT162b2, with the aim of showing at least 50% efficacy. BNT162b1 is a lipid-nanoparticle-formulated, nucleosidemodified mRNA encoding the receptor-binding domain of S. A phase 1/2 placebo-controlled, dose-escalation study on 45 adults, randomised to receive 2 doses of 10, 30 or 100 µg showed dose-dependent reactogenicity 14 . Antibodies recognising the receptor-binding domain and neutralising antibodies were also elicited in a dose-dependent manner and increased after a second dose. This vaccine was subsequently compared to a second version, BNT162b2, encoding stabilised, membrane-anchored full-length prefusion S 15 . Interestingly, both vaccines elicited similar dose-responses in younger and older adults, and BNT162b2 was selected for further clinical development because of improved safety. Similarly, mRNA-1273 also codes for stabilised prefusion S. A phase 1, open-label trial in young adults showed acceptable safety and reactogenicity and the induction of neutralising antibodies after two injections 16 . This vaccine was also tested for safety in older adults, age 56 to 70 and above 17 , using two doses of 25 µg or 100 µg. In this population, adverse events were moderate for both dosages, but the 100-µg dose was chosen because it induced stronger neutralising antibody titres. The vaccine also induced CD4 + T cell responses, including IFN-, IL-2 and TNF- production. In addition to these studies, more than 200 trials have been registered so far on ClinicalTrials.gov (https://clinicaltrials.gov/ct2/results?term=COVID-19+vaccine&Search=Search), but safety, efficacy or immunogenicity data are lacking for most of them. Besides SARS-CoV-2-specific vaccines, these trials also include studies on heterologous vaccines, in particular the Bacillus Calmette-Guérin (BCG). BCG is known to induce heterologous protection, especially against respiratory infections, by the generation of trained innate immunity, and may therefore potentially protect against COVID-19 18 .

Vaccines take usually at least 10 to 15 years to be developed, due to the phasing of vaccine development, from pre-clinical to clinical phases 1, 2 and 3, the latter being the conclusive efficacy trial. These phases are usually conducted sequentially, as they become increasingly costly. Therefore, before engaging resources to the following phase, it is important to ensure that the data of the previous phase are convincing enough to warrant further development. Anti-COVID-19 vaccine development has proceeded at an unprecedented pace, as several phases are conducted simultaneously because of massive financial resources poured into vaccine development. Within months rather than years, more than 30 vaccines have entered the clinical development pipeline, including a dozen in phase 2/3 trials. Simultaneously, largescale manufacturing was launched before data on safety and efficacy were gathered to make safe and effective vaccines readily available. However, considering the width of the COVID-19 pandemic, mounting to close to 1,000,000 global deaths at the time this article was prepared, it remains uncertain whether enough vaccines will be available. Vaccine roll out will take time and is accompanied by difficult decisions about priorities as to who should receive the vaccines first 20 . Furthermore, accelerated vaccine development may also lead to confusion in the public perception and concern about safety and efficacy of anti-COVID-19 vaccines once approved, and about vaccines in general. Furthermore, there is a risk that anti-vaccine movements will use this opportunity to strengthen their position, which may have disastrous consequences, as vaccine hesitancy is regarded as one of the 10 most important global health threats today. Yet, the widespread use of safe and efficacious anti-COVID-19 vaccine is the only hope for us to return to a "normal" life. J o u r n a l P r e -p r o o f 

Resident memory CD8+ T cells in the upper respiratory tract prevent pulmonary influenza virus infection

Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, nonrandomized, first-in-human trial

Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomized, double-blind, placebo-controlled, phase 2 trial

Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomized controlled trial

Safety and immunogenicity of an rAd26 and rAd5 vectorbased heterologous prime-boost COVD-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia

Russian SARS-CoV-2 vaccine

Effect of an inactivated vaccine against SARS-CoV-2 on safety and immunogenicity outcomes, Interim analysis of 2 randomized clinical trials

Phase 1/2 study of COVID-19 RNA vaccine BNT162b1 in adults

RNA-based COVID-19 vaccine BNT162b2 selected for a pivotal efficacy study. medRxiv

An mRNA vaccine against SARS-CoV-2 -preliminary report

Safety and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adults

Covid-19: vaccine roll out could take a year and will require difficult priority decisions

Reassuring the public and clinical community about the scientific review and approval of a COVID-19 vaccine