10 Dec Episode 93 Chinese and Indian vaccines

Episode 93: Analysis of the Chinese and Indian COVID vaccine forerunners

Dear colleagues,

We are overwhelmed with (very partial and superficial) information on COVID vaccines these days, but our info is dominated by the “Western” views.  I was wondering what information I could find about China and India, two emerging giant vaccine producing countries.  As you will see below, there is quite some nicely published info on some of the Chinese fore-runners, but very little, if anything about India.  

For China, in this episode, I will focus on the inactivated and Adeno 5 vaccines, because there is a lot of interesting scientifically published info on those candidates and they are being rolled out over the world already. I will discuss more innovative approaches in a next Episode.     

1. Chinese whole inactivated vaccines

SinoVac is developing the inactivated “Coronavac”, which was first described by Gao on 3 July in Science as PicoVacc, based on the CN(0)2 strain.  I mentioned it already before: it is a very classical preparation (shown in slide 2)  that induced neut Ab titers in mice, rats and non-human primates, at levels comparable with convalescent patients and that nicely protected against homologous challenge in macaques, after three injection (0-7-14 days) with either 3 or 6 µg dose. T cell responses were not evaluated.

In the phase ½ trial (slide 3) 3 and 6 µg dose as well 0-14 and 0-28 days were compared.  The results are shown in Fig 3, from which the authors conclude to go for the 3 µg day 0-28 schedule. In the discussion they indicate that the neut titers induced  4 weeks after last vaccination are about 24-65 GMT, which is clearly lower than what they observe in convalescent patients (mean 164 GMT).

One of the limitations is that only healthy adults (18-59) were included.  About T cell responses, the authors first state that T cell responses were not evaluated, but later in the Discussion they write: T-cell responses measured by ELISpot were low in participants who were given vaccine.

They also indicate that three phase 3 clinical trials are ongoing in Brazil, Indonesia, and Turkey  

Sinopharm is developing two inactivated vaccines in collaboration with Wuhan Institute of Biological Products and Beijing Institute of Biological Products. Both vaccine candidates are currently in Phase 3 trials in the United Arab Emirates.

Bejing Biological Institute of Biological Products

Very nice and convincing data on the preclinical development with all details and QC are given (slide 4-6 Hui Wang Cell Aug 2020), in fact comparable with the former PiCoVacc-Coronavac.

In phase 1 and 2 trials (Shengli Xia Lancet Inf Dis Oct 2020), there was a more extensive comparison between various doses, various time intervals in both younger (< 60) and older (> 60) adults, as shown in the slides.  Fig 2 slide 7 clearly shows that on day 14 most of the younger participants (> 80 %) had seroconverted, while this frequency of seroconversion was only seen at day 28 (just before the booster) in the participants of > 60 years.  These older participants also tended to present more side effects, but without serious consequences. 

Their final conclusion is

Humoral responses against SARS-CoV-2 were induced in all vaccine recipients on day 42.

Two-dose immunisation with 4 μg vaccine on days 0 and 21 or days 0 and 28 achieved higher neutralising antibody titres than the single 8 μg dose or 4 μg dose on days 0 and 14.

Wuhan Institute of Biological Products:

No preclinical data have been published, as far as I can see. The product is briefly described in the JAMA paper:  WIV04 strain, which is generated like all other inactivated SARS-CoV-2 vaccines: cultivated on Vero, inactivated with beta-propiolactone, ultra-filtrated and adsorbed in AlOH

The results of phase 1 and 2 trials in healthy adults (18-59 years)

- In phase 1 study three intramuscular injections (days 0, 28 and 56) were given with acceptable side effects and 14 days after the third vaccination (day 70), a high NAb response was observed in almost all participants. (slide 8)

- In phase 2 two 2-dose regimens were compared: 2nd dose after 2 or 3 weeks  with only one "medium" (5 µg) dose of phase 1. Again, nearly all participants developed NAb, but the 3 weeks Interval was superior In terms of antibody levels. (slide 9)

Acknowledged and acceptable limitations (as reiterated in the “Comments” by Mark Mulligan) included

• the absence of data for persistence of antibody response,
• the absence of longer-term safety information,
• lack of comparison of the neut titers with a reference group (e.g. convalescent patients)
• lack of data on T responses.

A paper in CID by Yanchun Che describes still another, but very similar inactivated vaccine based on the KMS-1 strain, developed by the Institute of Medical Biology (IMB), Chinese Academy of Medical Sciences (CAMS).  Based on the results on slide 10,  they conclude that a high dose (150 “Elisa Units”) with the day 0, 14 procedure would be best.  All in all this paper is less well documented than the former ones. 

2. Cansino: recombinant SARS-CoV-2 Spike in Human Adeno 5 vaccine

Feng-Cai Zhu reports on phase 1 in Lancet (May 2020): 5 × 1010, 1 × 1011, and 1.5 × 1011 viral particles were administered once i.m. in adults (18-60).  Slide 11-12.

• Only in high dose group 100 % seroconvert and 75 % neut Ab.
• Multivariable analysis showed that high pre-existing Ad5 neutralizing antibody titers compromised the seroconversion of neutralizing antibody post-vaccination, regardless of the vaccine doses, and recipients aged 45–60 years seemed to have lower seroconversion of neut antibody compared with the younger recipients
• Pre-existing Adeno 5 Ab have also clear negative effect on T cell responses.

The high dose vaccine tended to be more immunogenic than the middle dose and low dose vaccines, it was also associated with a higher reactogenicity: severe fever, fatigue, dyspnoea, muscle pain, and joint pain were reported in some of the recipients.

The phase 2 trial in Lancet (July 2020) confirmed these data: slide 13

• More  immunongenic and more reactogenic at highest dose (1 X 10 11), which is 33%  lower than in phase 1
• Clear negative influence of preexisting antibodies to Ad 5 and advanced age (45-60)
• The authors suggest (but do not show evidence) that a second dose could be better

India’s vaccine portfolio in development: It is a real puzzle to find information. I identified only 1 published paper (on preclinical Mynvax).  To get a broader picture, I had to search on Indian newspapers and company websites.  

1. Bharat Biotech’s Covaxin:

India’s first vaccine against COVID-19 is an inactivated whole SARS-CoV-2

• Developed by Bharat BioTech, Indian Council of Medical Research (ICMR) and National Institute of Virology (NIV).
• The vaccine was found to generate robust immune responses, thereby preventing infection and disease in the primates upon high amount of exposure to live SARS-CoV-2 virus
• It has successfully cleared Phase I/II human trial (which have not been published as far as I can see) and is given permission for Phase III trial by DCGI (Drug Controller General of India).

2. Cadila’s ZyCoV-D vaccine:

It is India’s second vaccine, a type of DNA plasmid vaccine expressing SARS-CoV-2 S protein developed by Zydus Cadila Healthcare. After a successful phase 1 trial, the phase II trial of the is underway. (Anulekha Ray, 2020; CTRI/2020/07/026352, 2020).

3. Mynvax: recombinant Receptor Binding Domain that can be stored at 37°C for over a month.  According to a paper in JBC, two doses with the strong MF59 adjuvant elicit neutralizing antibody titers in guinea pigs that are comparable to other vaccines in the running (although no direct comparison is made).   

4. Gennova : self-replicating mRNA platform  for Spike: in collaboration with HDT Biotech Corp Seattle
5. Biological E: Ohio State Innovation Foundation is licensing novel live attenuated measles virus vectored vaccine candidates against SARS-CoV-2 developed by the Ohio State University College of Veterinary Medicine, exclusively to the company.
6. Covishield = Oxford AstraZenica: ChimpAdeno with recombinant Spike

7. Gamaleya = Russian combination of human recombinant Spike Adeno5 (like CanSino) + Adeno26 (like Janssen J&J)

My provisional conclusions:

• China and India have taken the lead in the development of inactivated COVID vaccines.  The safety and immunogenicity record of these “traditional” vaccines is well-known and, based on the published work, they could offer a rather cheap and robust solution to be rolled out over the world.  A disadvantage is that at least two doses have to be applied, a cold chain is still needed and presumably they will not induce life-long immunity. Another  possible limitation is a rather weak T cell response, which may limit the durability and efficacy of the immune response as well. 
• It is surprising that none of the “Western companies” has made any attempt to develop an inactivated COVID vaccine, although it is apparently straightforward, they have over 60 years of experience and they are really “giving away” the markets of the Global South to Chinese and Indian companies.  An interesting turning point in health geo-politics?
• Talking about geo-politics, China seems to be faster and more independent than India.  The latter country has a much more limited “own portfolio” of rather “simple” vaccines and is collaborating (in-licensing) more advanced technology from Western countries and Russia.      

• The Adenovirus platform  has the theoretical advantage of inducing both T and B cell responses, but after one dose, these responses were rather weak. Ad5, as developed in China, is not a superior choice, because vaccine oriented immunogenicity is limited by pre-existing antibodies to the vector (a very prevalent serotype) and at high doses there is also more reactogenicity.  It is unclear whether a second dose would be useful. 
• The Ad26 (J&J) and Chimp Adeno (AstraZenica) would suffer less or not from pre-existing immunity, but in both phase III trials there have been unexplained interruptions due to side effects. The results communicated by AstraZenica, suggest that it was better to give a low first dose as “prime”, which is a bit suspect.  In fact, it looks as even the Chimp virus (with no pre-existing immunity) may sensitize too much after the first full “prime” dose, resulting in vector-specific antibodies,  which then strongly reduce the wanted stronger response to the “booster” dose of the vaccine antigen. 
• In fact, the “Russian solution” to combine Ad5 and Ad26 should theoretically be better than Ad5 alone and could be equivalent or superior to two doses of either Ad26 or ChAd.

• In the experimental vaccinology, it is known for quite some time that you reach superior responses by an ‘heterologous prime-boost”.  Usually priming with DNA (or mRNA) and boosting with either protein, inactivated virus or recombinant vectors gives better T and B responses and stronger protection than repeated “homologous” vaccination (twice or three times the same format: DNA, protein…). Obviously, for scientific and regulatory reasons, it was not possible to adopt this prime-boost strategy immediately for a new human virus, but it is very likely that it will be applied in the future, if it turns out that the immunity is short-lived or insufficient, especially in the vulnerable elderly, which clearly react suboptimal to various vaccines.     

Best wishes,

Guido