Since the beginning of this pandemic many of us have been wondering: when are we going to get a vaccine against SARS-CoV2? The development of a new, safe and efficient vaccine is a defined, rigorous process. The process is essentially the same leading to the discovery of a new drug.
Briefly, the development of a new vaccine starts with a discovery phase, aimed at exploring the biology of the pathogen and designing the vaccine. Vaccines can be protein-based, meaning that a synthetic viral protein is introduced in the human body to teach the immune system to react against future infections; DNA or RNA-based, in which the immune system is instructed by the injection of viral DNA/RNA which will be used by the cell to produce the viral protein; with the inactivated pathogen that, while unable to trigger the infection, will be capable to instruct the immune system against future infections.
The discovery phase is followed by a pre-clinical phase, in which the vaccine safety and efficacy (ability to induce an immune response) is tested in in vitro systems (cell and tissue cultures), and in animal systems: in few words, the pre-clinical phase aims at testing whether the new vaccine works.
If results of the pre-clinical phase are promising, the study is approved to proceed to the clinical testing.
Phase I of the clinical testing includes few subjects and aims at testing in humans safety of the vaccine, efficacy –namely the ability and extent of the immune system response elicited (immunogenicity)–, the optimal dose and the method of administration.
If phase I results are encouraging, the vaccine enters phase II. Phase II aims at further extending knowledge on safety and immunogenicity; a larger number of subjects is involved, including categories at high risk of developing the disease.
Vaccines successfully passing through phase II, enter phase III. Phase III involves thousands of people, and is mainly aimed at finding potential rare side effects (which may not be detectable in smaller groups tested). Efficacy is assessed as well, namely whether the vaccine actually prevents the disease.
For human testing, usually vaccinated people live their life normally, exposing themselves to the pathogen. However, some vaccine trials may proceed by a so-called “challenge model” in which, after vaccination, volunteers are injected with the pathogen –possibly exploiting an attenuated form– to test whether they are protected1. After approval, vaccines are produced and administered to the general population: the vaccine is released. Some studies may include also a phase IV testing, after approval, aimed at continuing assessing safety, efficacy, and other potential uses of the vaccine2.
A number of vaccines are currently under investigation against covid-19, several of them already in advanced phases of clinical testing. Among these we can mention the ChAdOx1 nCoV-19 (AZD1222), developed by the University of Oxford and Astra Zeneca, which also involves the Irbm of Pomezia, and the Ad5-nCoV, developed by the Beijing Institute of Biotechnology (Beijing, China) and CanSino Biologics, and whose results were recently published in The Lancet journal; the mRNA-1273, developed by the National Institute of Allergy and Infectious Diseases and Moderna; the BNT162, developed by BioNTech RNA Pharmaceuticals and Pfizer.
The ChAdOx1 nCoV-19 (AZD1222)3 is a DNA-based vaccine (using chimpanzee adenovirus-based vector), expressing SARS-CoV2 Spike protein. Pre-clinical studies had shown the ability of this vaccine to elicit immunogenicity in mice and to confer protection –with significantly lower viral load and no pneumonia compared to control– against low respiratory tract infection in non-human primates after high doses of SARS-CoV2 injection (results of this study were published on bioRxiv.org4).
The trial involved 1077 healthy adults (median age of participants was 35 years, 50% males) in UK. Vaccines were administered as a single intramuscular injection. Results are encouraging, supporting further clinical testing: i) Safety: mild to moderate adverse reactions were observed in 67% of participants and reduced by paracetamol administration. No serious adverse events were observed, demonstrating overall safety of the vaccine. ii) The vaccine immunogenicity was confirmed as well: anti-Spike protein antibodies were detected at day 28 (by ELISA) and remained elevated until day 56. Few participants received a second injection to boost immunogenicity. After the second injection, all subjects showed in vitro neutralizing activity against SARS-CoV2. Importantly, the authors observed a marked increase of SARS-CoV2-specific T-cell response*** after vaccination, starting from day 7 and up to day 56. However, a longer monitoring period and assessment of vaccine safety and efficacy in older age people groups are needed.
The Ad5-nCoV5 is a DNA-based vaccine (using an adenovirus 5 vector) expressing the gene of the viral Spike protein. The phase II trial, which was conducted in China, involved 508 healthy adults (50% males), mean age 39 years old, who received a single intramuscular injection in the arm. Two different doses were tested.
Results support the safety (especially at the lower dose) and efficacy of the vaccine: i) safety: adverse reactions were observed in about 70% of the participants injected with both doses, within 14 days from vaccination. However, severe adverse effects were observed in 9% of the participants injected with higher doses and in one participant only injected with the lower dose. Anyway, adverse effects resolved in a short time (no more than 48h) and no serious adverse reaction were observed. ii) Efficacy: vaccine injection induces significant immune response in the majority of participants after one single injection; indeed, antibodies were detected –by ELISA test– against RBD (receptor binding domain, region of the viral Spike protein) of the virus. These antibodies showed, in in vitro tests, a neutralizing activity against SARS-CoV2 28 days after injection of both doses of the vaccine, and increased T cell response was observed at day 28. However, it is currently unknown whether the vaccine is actually able to protect from SARS-CoV2 infection, as neutralizing tests have been done only in vitro and none of the participants was exposed to SARS-CoV2 infection; it is currently unknown whether the antibodies generated are maintained (as in patients with mild infection antibodies largely decrease a month after infection); efficacy may partially depend on previous exposure to adenoviruses (which are the vectors of the vaccine).
The mRNA-12736 is an RNA-based vaccine, coding for the Spike protein of SARS-CoV2, encapsulated in lipidic nanoparticles. The phase I trial enrolled 45 healthy adults, who received two injections. Different doses of the vaccine were tested. i) Safety: Adverse events were more frequent and severe with higher doses and after the second vaccination: no serious adverse effects were observed, however, 33% of the participants who received the lower dose, 67% who received the “intermediate” dose, and 53% of those who received the highest does showed mild to moderate adverse effects, mostly after the second injection. ii) Immunogenicity: the vaccine was immunogenic, inducing RBD-specific antibody production and high neutralizing activity against SARS-CoV2 virus (two-dose seems necessary) in all participants. The lower doses stimulated Spike protein-specific T cell response. Even though the durability of the response still needs to be evaluated, as well as actual protection from SARS-CoV2 infection, safety and immunogenicity data support further clinical testing.
The BNT1627 is an RNA-based vaccine encoding the RBD of the viral Spike protein encapsulated in a lipid nanoparticle. The study enrolled 45 healthy adults, who received two doses of the vaccine. Safety: Mild to moderate, transient adverse reactions were observed. Immunogenicity: RBD-specific antibodies were detected, with in vitro neutralizing activity against SARS-CoV2, which increased at increasing doses administered and after the second injection. Results support further clinical evaluation of this vaccine.
Although none of these vaccines has been tested yet for its ability to actually prevent the disease, measurement of neutralizing activity has been shown to correlate with protection for other respiratory viruses, and is generally accepted as a marker of in vivo antibody response. Therefore, all the four candidates appear promising. Which one will win the race?
***Infections elicit pathogen-specific immune responses, which include the humoral response (responsible for antibody production) and the cell-mediated response. Cell-mediated response involves T cells. Many new vaccines are designed to induce also a T cell response (in addition to the humoral response) to help the antibody-mediated response, to directly contribute to pathogen clearance, or to activate other immune cells (such as macrophages and neutrophils).
References. 1. Human Challenge Trials for Vaccine Development: regulatory Considerations. World Health Organization. EXPERT COMMITTEE ON BIOLOGICAL STANDARDIZATION. Geneva, 17 to 21 October 2016. 2. The Children's Vaccine Initiative: Achieving the Vision. 3. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. Folegatti, Ewer, […]Green, Douglas, Hill, Lambe, Gilbert, Pollard, on behalf of the Oxford COVID Vaccine Trial Group. The Lancet 2020. 4. ChAdOx1 nCoV-19 vaccination prevents SARS-CoV-2 pneumonia in rhesus macaques. Neeltje van Doremalen, Teresa Lambe, […] Sarah C. Gilbert, Vincent J. Munster. bioRxiv.org 2020. 5. Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial. Feng-Cai Zhu, Xu-Hua Guan, […], Wei Chen. The Lancet 2020. 6. An mRNA Vaccine against SARS-CoV-2 — Preliminary Report. L.A. Jackson, […] J.H. Beigel, for the mRNA-1273 Study Group. The New England Journal of Medicine. 7. Phase 1/2 study of COVID-19 RNA vaccine BNT162b1 in adults. Mark J Mulligan, […], Kathrin U Jansen. Nature 2020.