An update on potential SARS-CoV-2 vaccines

By Dr Mark Thomas, Associate Professor in Infectious Diseases, University of Auckland

17 September 2020

A safe, effective vaccine is essential for New Zealand’s long-term response to the COVID-19 epidemic. In the absence of prolonged, widespread, community spread almost everyone is susceptible to infection. A successful immunisation program will remove that risk. The overwhelming majority of people infected with SARS-CoV-2 recover from illness and eliminate the infection1, and only extremely rarely do people suffer a second episode of infection, which usually is brief and asymptomatic, suggesting a relatively low risk of onward transmission2. These features clearly indicate that strongly protective immune responses are the usual result of infection. While it appears that the immune responses following severe disease are a little stronger than those following mild disease or asymptomatic infection1, it has also been shown that infection results in generation of strong memory lymphocyte responses that prime the immune system to produce very effective responses upon re-exposure to the virus3.

The development of vaccines against SARS-CoV-2 has been greatly helped by the previous efforts to develop vaccines against the closely related SARS and MERS coronaviruses4. Studies of SARS-CoV-2, and the SARS and MERS viruses, have shown that spike proteins, projecting from the surface of these viruses, bind to receptor molecules on the surface of respiratory epithelial cells, initiating viral entry into these cells, followed by viral replication2. Infection with SARS-CoV-2 results in antibodies which bind to various regions of the spike proteins, including the region which binds to the ACE2 receptor. When SARS-CoV-2 is exposed to these antibodies the virus is 'neutralised' - it is unable to enter and infect respiratory epithelial cells5. The spike proteins are the viral antigens most commonly used in the SARS-CoV-2 vaccines under development and testing. In this respect these vaccines are analogous to Hepatitis B vaccines, which contain Hepatitis B surface antigen (HBsAg), the “spike protein” of hepatitis B virus.

Figure 1. A schematic representation showing a SARS-CoV-2 virus with spike proteins projecting out of the viral surface (A), a virus attached to an ACE2 receptor on the surface of a respiratory epithelial cell (B), antibody to the viral spike protein stimulated either by natural infection or by vaccination (C), and a virus coated with antibody bound to the viral spike proteins which prevents the virus attaching to, and then infecting, a respiratory epithelial cell (D).

Many studies, of large numbers of people who have been infected with SARS-CoV-2, have shown that they almost always produce antibody against the spike proteins, and that the concentration of these anti-spike antibodies in the patient’s serum correlates very strongly with the ability of the patient’s serum to neutralise the virus, ie. to prevent viable virus from attaching to and infecting target cells in vitro6. Similar studies show that immunisation with vaccines containing SARS-Cov-2 spike proteins can generate concentrations of anti-spike antibodies similar to those that occur in patients following severe disease (7,8). In a recent study, of almost 60 vaccinated volunteers, who received a spike protein plus adjuvant vaccine on days 0 and 21, the mean concentration of neutralising antibodies in vaccine’s serum on day 35, was approximately 3,000 times higher than the concentration required to neutralise the virus in vitro7. The next step, currently underway with some vaccines, is to see whether these strong vaccine-induced immune responses, do confer protection against disease in people enrolled in large randomised trials. It seems very likely to me that these vaccine efficacy studies will show a very high level of protection against COVID-19 disease.

Concern has frequently been expressed that declining concentrations of antibody in serum, either following natural disease, or following vaccination, will mean that disease-induced, or vaccine-induced, immunity will be short lived. However, serum concentrations of antibody commonly fall following either disease or vaccination, but immunity persists. This is because large numbers of memory lymphocytes were produced at the time of the initial immune response, and these long-lived memory cells ensure a rapid powerful immune response on re-exposure to the same antigens. A familiar example is that of immunity to hepatitis B virus. Any person who has generated an adequate immune response to hepatitis B vaccine, as demonstrated by a serum anti-HBsAg antibody concentration ≥10 IU/L, remains protected against hepatitis B virus disease, even if their antibody concentration subsequently is undetectable. Patients with no detectable antibody may have a brief period of sub-clinical infection, but their rapid powerful immune responses eliminate the infection before disease can occur. It seems very reasonable to assume that vaccine-induced immunity to SARS-CoV-2 might not provide absolute protection against infection, but is very likely to provide almost absolute protection against disease, even many years after vaccination.

Two SARS-CoV-2 vaccines, which might be used in New Zealand in the near future are discussed briefly below.

The Australian government has recently signed agreements with: (i) University of Oxford and Astra Zeneca, (ii) University of Queensland, and (iii) Commonwealth Serum Laboratories (CSL) which has a long history of vaccine production in Australia. These agreements will allow CSL to produce 30 million doses of the AZD1222 vaccine, developed by Astra Zeneca in collaboration with the University of Oxford, and 51 million doses of the V451 vaccine, developed by the University of Queensland. It has been suggested that these vaccines will have completed immunogenicity, safety, and efficacy testing, and be available for use, in early 2021 (AZD1222) and mid 2021 (V451). New Zealand may have the opportunity to purchase one or both of these vaccines manufactured in Australia.

The AZD1222 vaccine, developed by Astra Zeneca and University of Oxford, contains 5X1010 chimpanzee adenovirus viral particles, each of which carries the gene for the SARS-CoV-2 spike protein. After vaccination the adenovirus attaches to and infects cells, which then use the gene as instructions to synthesise the SARS-CoV-2 spike protein. The AZD1222 vaccine was given as a single dose to 533 healthy adult volunteers, and shown to stimulate antibody responses that were similar to those seen in patients who had recovered from COVID-19 illness. The vaccine commonly caused pain at the injection site and other mild to moderate systemic adverse effects in the two days immediately following vaccination8.

The University of Queensland vaccine (V451) contains the SARS-CoV-2 spike protein, plus an adjuvant (MF59). This vaccine has been shown to induce strong neutralising antibody responses in animals, and immunogenicity and safety studies in human volunteers have started in Australia.

A large number of other vaccines are under development9. One, the Russian “Sputnik V” vaccine has recently been distributed, without first undergoing large studies of its efficacy in preventing COVID-19 disease. The Sputnik V vaccine is very similar to the AZD1222 vaccine, in that it uses adenoviruses as vectors to transport the gene which codes for the SARS-CoV-2 spike protein into the cells of the vaccinated person, which then synthesise the SARS-CoV-2 spike protein, and thus stimulate immune responses against the spike protein10

It seems likely that some vaccines, which have been shown in large studies to be safe and efficacious, will be available for purchase by the middle of 2021. Hopefully New Zealand will be able to select a safe effective vaccine to purchase. And hopefully we will achieve successful vaccination in at least 70-80% of the population, and thus prevent community transmission of SARS-CoV-2 in New Zealand.