REPORT VACCINE COVID-19 : AZD1222 SARS-CoV-2 and competitors

A COVID-19 vaccine under trial in the UK induces a strong immune response in both parts of the immune system within 14 days of administration.

Between April 23 and May 21, 2020, 1077 participants were enrolled and assigned to receive either ChAdOx1 nCoV-19 (n=543) or MenACWY (n=534), ten of whom were enrolled in the non-randomised ChAdOx1 nCoV-19 prime-boost group.

Local and systemic reactions were more common in the ChAdOx1 nCoV-19 group and many were reduced by use of prophylactic paracetamol, including pain, feeling feverish, chills, muscle ache, headache, and malaise (all p<0·05).

There were no serious adverse events related to ChAdOx1 nCoV-19.

In the ChAdOx1 nCoV-19 group, spike-specific T-cell responses peaked on day 14 (median 856 spot-forming cells per million peripheral blood mononuclear cells, IQR 493–1802; n=43).

Anti-spike IgG responses rose by day 28 (median 157 ELISA units [EU], 96–317; n=127), and were boosted following a second dose (639 EU, 360–792; n=10).

Neutralising antibody responses against SARS-CoV-2 were detected in 32 (91%) of 35 participants after a single dose when measured in MNA₈₀ and in 35 (100%) participants when measured in PRNT₅₀.

After a booster dose, all participants had neutralising activity (nine of nine in MNA₈₀ at day 42 and ten of ten in Marburg VN on day 56). Neutralising antibody responses correlated strongly with antibody levels measured by ELISA (R²=0·67 by Marburg VN; p<0·001).

COVID-19 Vaccines in Development

• Multiple vaccines are under development: approximately 24 are in clinical trials (Table 1) and 140 in preclinical evaluation.[1]
• For overview of trial design, see Clinical Trial Phases and Definitions
• Among those with the greatest potential for speed are DNA- and RNA-based platforms, followed by those for developing recombinant-subunit vaccines.
• RNA and DNA vaccines can be made quickly because they require no culture or fermentation, instead using synthetic processes.

Recent updates: BioNTech/Pfizer announced the U.S. government ordered 100 million doses of BNT162 for $1.95 billion as part of the U.S. Warp Speed program. A Phase 2b/3 safety and efficacy trial for the vaccine begins later this month.[2] University of Oxford ChAdOx1 nCoV-19 vaccine Phase 1/2 trial published in Lancet.[3] In adults age 18-55 a single dose elicited both humoral and cellular responses against SARS-CoV-2, with a booster immunization augmenting neutralizing antibody titres. No serious adverse effect were reported; mild-moderate side effects were common. Results support continued evaluation in Phase 3 trials that are already underway in Brazil, South Africa, and the UK. CanSino Biologics Adenovirus Type 5 vectored vaccine Phase 2 trial published in Lancet.[4] In adults age ≥ 18 a single dose induced cellular or humoral immune responses at day 28 post vaccination in 91–95% of recipients depending on the dose. Mild-moderate side effects were common; Grade 3 adverse effects were seen in 9%. Moderna mRNA-1273 vaccine Phase 1 study published in New England Journal of Medicine.[5] Forty-five adults age 18–55 were tested with one of three dose levels given as 2 vaccinations 28 days apart. All subjects produced antibodies and neutralizing activity on par with natural infection. Mild-moderate side effects were common. Novavax receives U.S. Warp Speed funding for NVX-CoV2373 protein-based vaccine development and clinical trials.[6] BioNTech and Pfizer report success of mRNA-based vaccine BNT162b1 in Phase 1/2 trial.[7],[8] INOVIO reports success of DNA-based vaccine INO-4800 in Phase 1 trial.[9] CanSino Biologics received Military Specially-needed Drug Approval (軍隊特需藥品批件) for non-replicating adenovirus vaccine Ad5-nCoV for use in the Chinese military.[10]

COVID-19 Vaccines in Clinical Trials

Platform	Type	Developer	Current stage
Non-Replicating Viral Vector	Weakened adenovirus (ChAdOx1-S; AZD1222)	University of Oxford/ AstraZeneca	Phase 3 ISRCTN89951424Phase2b/3 NCT04400838Phase 1/2 PACTR202006922165132; 2020-001072-15; Results in Lancet[11]
Inactivated	Inactivated + alum (CoronaVac; formerly PiCoVacc)	Sinovac	Phase 3 NCT04456595Phase 1/2 NCT04383574 ; NCT04352608; Results in Science[12]
RNA	LNP-encapsulated mRNA (mRNA-1273)	Moderna/ NIAID	Phase 3 NCT04470427Phase 2 NCT04405076Phase 1 NCT04283461; Results in NEJM[5]
Inactivated	Inactivated	Wuhan Institute of Biological Products/ Sinopharm	Phase 3 ChiCTR2000034780Phase 1/2 ChiCTR2000031809
Inactivated	Inactivated (BBIBP-CorV)	Beijing Institute of Biological Products/ Sinopharm	Phase 3 ChiCTR2000034780Phase 1/2 ChiCTR2000032459
Non-Replicating Viral Vector	Adenovirus Type 5 Vector (Ad5-nCoV)	CanSino Biological Inc./ Beijing Institute of Biotechnology	Phase 2 NCT04341389; Results in Lancet[4]Phase 1 NCT04313127; Results in Lancet[11]
DNA	DNA plasmid vaccine with electroporation (INO-4800)	Inovio Pharmaceuticals / International Vaccine Institute	Phase 1/2 NCT04336410; NCT04447781
Protein Subunit	Recombinant SARS CoV-2 glycoprotein nanoparticle vaccine adjuvanted with Matrix M (NVX-CoV2373)	Novavax	Phase 1/2 NCT04368988
RNA	3 LNP-mRNAs (BNT162)	BioNTech/ Fosun Pharma/ Pfizer	Phase 1/2 2020-001038-36NCT04368728; Preprint results[7],[8]
Inactivated	Whole-Virion Inactivated	Bharat Biotech	Phase 1/2 CTRI/2020/07/026300
Protein Subunit	RBD-based	Kentucky Bioprocessing, Inc	Phase 1/2 NCT04473690
Inactivated	Inactivated	Institute of Medical Biology, Chinese Academy of Medical Sciences	Phase 1 NCT04412538
DNA	DNA Vaccine (GX-19)	Genexine Consortium	Phase 1 NCT04445389
DNA	DNA plasmid vaccine	Cadila Healthcare Limited	Phase 1/2 CTRI/2020/07/026352
DNA	DNA plasmid vaccine + Adjuvant	Osaka University/ AnGes/ Takara Bio	Phase 1 JapicCTI-205328
Non-Replicating Viral Vector	Adenovirus-based (Gam-COVID-Vac)	Gamaleya Research Institute	Phase 1 NCT04436471NCT04437875
Protein Subunit	Native like Trimeric subunit Spike Protein vaccine (SCB-2019)	Clover Biopharmaceuticals Inc./ GSK/ Dynavax	Phase 1 NCT04437875
Protein Subunit	Adjuvanted recombinant protein (RBD-Dimer)	Anhui Zhifei Longcom Biopharmaceutical/ Institute of Microbiology, Chinese Academy of Sciences	Phase 1 NCT04445194
Protein Subunit	Recombinant spike protein with Advax™ adjuvant	Vaxine Pty Ltd/ Medytox	Phase 1 NCT04453852
Protein Subunit	Molecular clamp stabilized Spike protein with MF59 adjuvant	University of Queensland/ CSL/ Seqirus	Phase 1 ACTRN12620000674932p
RNA	LNP-nCoVsaRNA	Imperial College London	Phase 1 ISRCTN17072692
RNA	mRNA	Curevac	Phase 1 NCT04449276
RNA	mRNA	People’s Liberation Army (PLA) Academy of Military Sciences/Walvax Biotech	Phase 1 ChiCTR2000034112
VLP	Plant-derived VLP	Medicago Inc./ Université Laval	Phase 1 NCT04450004
†Adapted from Draft landscape of COVID-19 candidate vaccines. WHO. 21 July 2020.[1]LNP = lipid nanoparticle; RBD = receptor-binding domain; mRNA = messenger RNA; VLP = virus-like particlesRecipient of U.S. Operation Warp Speed Funding[13],[14]

COVID-19 Vaccine Trial Phases and Definitions

Preclinical Testing

Vaccine given to animals such as mice or monkeys to see if it produces an immune response.

Phase I

Vaccine given to a small number of people to test safety and dosage as well as to confirm that it stimulates the immune system.

Phase II

Vaccine given to hundreds of people split into different age or risk groups groups to see if the vaccine acts differently in them. These trials further test the vaccine’s safety and ability to stimulate the immune system.

Phase III

Vaccine given to thousands of people and wait to see how many become infected, compared with volunteers who received a placebo. These trials can determine if the vaccine protects against the coronavirus.

Approval

Regulators in each country review the trial results and decide whether to approve the vaccine or not. During a public health emergency, a vaccine may receive Emergency Use Authorization (EUA) before getting formal approval.

Warp Speed

The U.S. government’s Operation Warp Speed program is expected to name five or more vaccine projects to receive billions of dollars in federal funding before there’s proof that the vaccines work.

Combined Phases

Some coronavirus vaccines are now in combined phase trials to speed evalutation. For instance, many Phase I/II trials are underway to test a vaccine for the first time on hundreds of people.

AZD1222 SARS-CoV-2 Vaccine Description

The AZD1222 coronavirus vaccine candidate, formerly known as ChAdOx1 nCoV-19, is made from a virus (ChAdOx1), which is a weakened version of a common cold virus (adenovirus) that causes infections in chimpanzees, that has been genetically changed so that it is impossible for it to grow in humans.

Genetic material has been added to the ChAdOx1 construct, which is used to make proteins from the SARS-CoV-2 coronavirus called Spike glycoprotein (S). This protein is usually found on the surface of SARS-CoV-2 and plays an essential role in the infection pathway of the SARS-CoV-2 virus.

The SARS-CoV-2 coronavirus uses its spike protein to bind to ACE2 receptors on human cells to gain entry to the cells and cause an infection.

After vaccination, the surface spike protein is produced, priming the immune system to attack the coronavirus if it later infects the body, and causes COVID-19 disease.

By vaccinating with AZD1222 (ChAdOx1 nCoV-19), these researchers are hoping to make the body recognize and develop an immune response to the Spike protein that will help stop the SARS-CoV-2 virus from entering human cells and therefore prevent infection.

Vaccines made from the ChAdOx1 virus have been given to more than 320 people to date and have been shown to be safe and well-tolerated, although they can cause temporary side effects, such as temperature, headache or a sore arm.

A preliminary report published on July 20, 2020, of a phase 1/2 study showed a single dose of AZD1222 resulted in a 4-fold increase in antibodies to the SARS-CoV-2 virus spike protein in 95% of participants one month after injection.

The AZD1222 vaccine candidate has progressed into late-stage Phase II/III clinical trials in more than 10,000 people from across the UK.

If the vaccine is proven to be safe and effective, the first doses to be produced under this agreement are anticipated to be available in early 2021. Vaccines will be released on a rolling basis as production is completed, and the full quota of 300 million doses is expected to be available by July 2021.

The AZD1222 vaccine was developed by Oxford University’s Jenner Institute, working with the Oxford Vaccine Group.

The Oxford Vaccine Centre’s COVID-19 vaccine trial is being run by the Jenner Institute and Oxford Vaccine Group. The team, who started work on developing a coronavirus vaccine candidate to prevent COVID-19 disease, began on January 20, 2020.

AZD1222 SARS-CoV-2 Vaccine Indication

The ChAdOx1 nCoV-19 vaccine candidate is being tested in clinical trials to prevent infection of SARS-CoV-2 which causes COVID-19 disease.

AZD1222 SARS-CoV-2 Vaccine Dosage

Biological: ChAdOx1 nCoV-19 – A single dose of 5×10^10vp of ChAdOx1 nCoV-19.

Biological: ChAdOx1 nCoV-19 boost – A single dose of 5×10^10vp of ChAdOx1 nCoV-19 followed by a boost dose of 2.5×10^10vp of ChAdOx1 nCoV-19.

Results

Between April 23 and May 21, 2020, 1077 participants were enrolled into the study and assigned to vaccination with either ChAdOx1 nCoV-19 (n=543) or MenACWY (n=534; appendix p 3); ten of these participants were enrolled in group 3, the prime-boost group, and thus were not randomly assigned. 88 participants were included in group 1, 412 in group 2, and 567 in group 4 (appendix p 3).

All randomised participants were vaccinated; one participant in the MenACWY group received the ChAdOx1 nCoV-19 vaccine (appendix p 3).

The median age of participants was 35 years (IQR 28–44 years), 536 (49·8%) participants were female and 541 (50·2%) were male, and the majority of participants (979 [90·9%]) were white (appendix p 4).

Baseline characteristics seemed similar between randomised groups (appendix p 4).56 participants in the ChAdOx1 nCoV-19 group and 57 in the MenACWY group received prophylactic paracetamol.

In those who did not receive prophylactic paracetamol, 328 (67%) of 487 participants in the ChAdOx1 nCoV-19 group and 180 (38%) of 477 participants in the MenACWY group reported pain after vaccination, which was mostly mild to moderate in intensity (appendix pp 5–7).

With prophylactic paracetamol, pain was reported by fewer participants: 28 (50%) in the ChAdOx1 nCoV-19 group and 18 (32%) in the MenACWY group. Tenderness of mostly mild intensity was reported in the ChAdOx1 nCoV-19 group by 403 (83%) participants without paracetamol and 43 (77%) with paracetamol, and in the MenACWY group by 276 (58%) participants without paracetamol and 26 (46%) with paracetamol (figure 1; appendix pp 5–7).

Fatigue and headache were the most commonly reported systemic reactions. Fatigue was reported in the ChAdOx1 nCoV-19 group by 340 (70%) participants without paracetamol and 40 (71%) with paracetamol and in the MenACWY group by 227 (48%) participants without paracetamol and 26 (46%) with paracetamol, whereas headaches were reported in the ChAdOx1 nCoV-19 group by 331 (68%) participants without paracetamol and 34 (61%) with paracetamol and in the MenACWY group by 195 (41%) participants without paracetamol and 21 (37%) participants with paracetamol.

Other systemic adverse reactions were common in the ChAdOx1 nCoV-19 group: muscle ache (294 [60%] participants without paracetamol and 27 [48%] with paracetamol), malaise (296 [61%] and 27 [48%]), chills (272 [56%] and 15 [27%]); and feeling feverish (250 [51%] and 20 [36%]).

In the of ChAdOx1 nCoV-19 group, 87 (18%) participants without paracetamol and nine (16%) participants with paracetamol reported a temperature of at least 38°C, and eight (2%) patients without paracetamol had a temperature of at least 39°C. In comparison, two (<1%) of those receiving MenACWY reported a fever of at least 38°C, none of whom were receiving prophylactic paracetamol (figure 1; appendix pp 5–7).

The severity and intensity of local and systemic reactions was highest on day 1 after vaccination (figure 1).Adjusted analysis of the effect of prophylactic paracetamol on adverse reactions of any severity in the first 2 days after vaccination with ChAdOx1 nCoV-19 showed significant reductions in pain, feeling feverish, chills, muscle ache, headache, and malaise (appendix pp 10–11).

All ten participants in the prime-boost group received their booster vaccine at day 28; solicited local and systemic reactions were measured in these participants for 7 days after both the prime and booster doses. The reactogenicity profile after the second dose appeared less severe in this subset, although the small number of participants in this group led to wide CIs (figure 2; appendix pp 8–9).

Unsolicited adverse events in the 28 days following vaccination considered to be possibly, probably, or definitely related to ChAdOx1 nCoV-19 were predominantly mild and moderate in nature and resolved within the follow-up period (appendix pp 12–15).

Laboratory adverse events considered to be at least possibly related to the study intervention were self-limiting and predominantly mild or moderate in severity (data not shown).

Transient haematological changes from baseline (neutropenia) were observed in 25 (46%) of 54 participants in the ChAdOx1 nCoV-19 group compared with three (7%) of 44 participants in the MenACWY group.

There was one serious adverse event in the MenACWY group consisting of a new diagnosis of haemolytic anaemia, occurring 9 days after vaccination. The participant was clinically well throughout the study.

The event was reported as a suspected unexpected serious adverse reaction relating to the MenACWY vaccine.In the ChAdOx1 nCoV-19 group, antibodies against SARS-CoV-2 spike protein peaked by day 28 (median 157 ELISA units [EU], IQR 96–317; n=127) and remained elevated to day 56 (119 EU, 70–203; n=43) in participants who received only one dose, and increased to a median of 639 EU (360–792) at day 56 in the ten participants who received a booster dose (figure 3).

Similar increases in serum antibody levels to both the spike protein and the receptor binding domain by day 28 and after a booster dose were observed when measured by MIA (appendix p 16).

Immunogenicity among those who were advised to take paracetamol prophylactically was similar to that seen among those who were not advised to use it prophylactically (data not shown).

In the PHE PRNT₅₀ assay, which determined the extent to which serum can be diluted and still reduce SARS-CoV-2 plaque formation by 50%, 35 (100%) of 35 participants achieved neutralising titres with a median titre of 218 (IQR 122–395) at day 28 and similar results were obtained with the PHE MNA₈₀ assay, with titres inducing 80% virus neutralisation achieved in 32 (91%) of 35 participants after one dose (median titre 51, 32–103), and in nine (100%) of nine participants after the booster dose (median titre 136, 115–241; figure 4; appendix pp 17–19).

In the Marburg VN assay, 23 (62%) of 37 recipients had neutralising antibodies that induced complete inhibition of the cytopathic effect caused by SARS-CoV-2 by day 56 after one dose, as did ten (100%) of ten participants after a booster dose, with a median titre of 29 (24–32; figure 4).

Titres from the PseudoNA assay and the Marburg VN assay correlated positively with other live virus neutralisation assay titres and with ELISA (PseudoNA R²=0·53 and Marburg VN R²=0·67; both p<0·001; Figure 4, Figure 5; appendix pp 20–21).

We included responses following natural exposure as a point of reference for vaccine response data, and found that vaccine-induced responses were in a similar range (figure 5).

Interferon-γ ELISpot responses against SARS-CoV-2 spike peptides peaked at 856 spot-forming cells per million peripheral blood mononuclear cells (IQR 493–1802; n=43) at day 14, declining to 424 (221–799; n=43) by day 56 after vaccination (figure 6).

A small number (four [4%] of 98) participants had neutralising antibody titres greater than 8 against SARS-CoV-2 spike protein before vaccination (Marburg VN) and 11 (4%) of 270 participants had high ELISA titres at baseline, representing possible prior asymptomatic infection.Before vaccination, only one (1%) of 98 participants who were tested had high titre (>200) neutralising antibodies against ChAdOx1.

Antibodies were detectable at a lower level in a further 18 (1%) participants, and in 79 (81%) participants there were no detectable anti-ChAdOx1 antibodies. We found no relationship between presence of low-level antibodies to ChAdOx1 on the day of vaccination and the ELISA titre to SARS-CoV-2 spike protein in those randomly assigned to receive ChAdOx1 nCoV-19 (appendix p 22).

---

References

1. Draft landscape of COVID-19 candidate vaccine. World Health Organization. [https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candid…]
2. Pfizer and BioNTech Announce an Agreement with U.S. Government for up to 600 Million Doses of mRNA-based Vaccine Candidate Against SARS-CoV-2. Businesswire. July 22, 2020. [https://www.businesswire.com/news/home/20200722005438/en/]
3. Folegatti PM et al. 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. Lancet. July 20, 2020. [https://doi.org/10.1016/S0140-6736(20)31604-4]
4. Zhu FC Guan XH Li YH et al. 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. Lancet. 2020; published online July 20. [https://doi.org/10.1016/S0140-6736(20)31605-6]
5. Jackson LA, Anderson EJ, Rouphael NG, et al. An mRNA Vaccine against SARS-CoV-2 – Preliminary Report. N Engl J Med. 2020.  [PMID:32663912]
6. U.S. Will Pay $1.6 Billion to Novavax for Coronavirus Vaccine. New York Times. July 7, 2020. [https://www.nytimes.com/2020/07/07/health/novavax-coronavirus-vaccine-warp…]
7. Phase 1/2 Study to Describe the Safety and Immunogenicity of a COVID-19 RNA Vaccine Candidate (BNT162b1) in Adults 18 to 55 Years of Age: Interim Report. medRxiv 2020.06.30.20142570; doi: https://doi.org/10.1101/2020.06.30.20142570
8. Sahin U et al. Concurrent human antibody and TH1 type T-cell responses elicited by a COVID-19 RNA vaccine. medRxiv 2020.07.17.20140533; https://doi.org/10.1101/2020.07.17.20140533]
9. INOVIO Announces Positive Interim Phase 1 Data For INO-4800 Vaccine for COVID-19. Press Release. June 30, 2020. http://ir.inovio.com/news-releases/news-releases-details/2020/INOVIO-Annou…
10. Recombinant Novel Coronavirus Vaccine (Adenovirus Type 5 Vector) Received Military Specially-needed Drug Approval. Hong Kong Stock Exchange Filing. June 25, 2020. https://www1.hkexnews.hk/listedco/listconews/sehk/2020/0629/2020062900123.…
11. Zhu FC, Li YH, Guan XH, et al. 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. Lancet. 2020;395(10240):1845-1854.  [PMID:32450106]
12. Gao Q, Bao L, Mao H, et al. Rapid development of an inactivated vaccine candidate for SARS-CoV-2. Science. 2020.  [PMID:32376603]
13. Fact sheet: explaining Operation Warp Speed. US Department of Health & Human Services. Published June 16, 2020. Accessed July 9, 2020. [https://www.hhs.gov/about/news/2020/06/16/fact-sheet-explaining-operation-warp-speed.html]
14. O’Callaghan KP, Blatz AM, Offit PA. Developing a SARS-CoV-2 Vaccine at Warp Speed. JAMA. 2020.  [PMID:32628244]
15. Deming ME, Michael NL, Robb M, et al. Accelerating Development of SARS-CoV-2 Vaccines – The Role for Controlled Human Infection Models. N Engl J Med. 2020.  [PMID:32610006]
16. Graham BS. Rapid COVID-19 vaccine development. Science. 2020;368(6494):945-946.  [PMID:32385100]
17. Lurie N, Saville M, Hatchett R, et al. Developing Covid-19 Vaccines at Pandemic Speed. N Engl J Med. 2020;382(21):1969-1973.  [PMID:32227757]